Brain Research Bulletin 97 (2013) 69–80

Contents lists available at ScienceDirect

Brain Research Bulletin

jo urnal homepage: www.elsevier.com/locate/brainresbull

Review

Roles of long noncoding RNAs in brain development, functional

diversification and neurodegenerative diseases

1 1 ∗

Ping Wu , Xialin Zuo , Houliang Deng, Xiaoxia Liu, Li Liu, Aimin Ji

Center for Drug Research and Development, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Long noncoding RNAs (lncRNAs) have been attracting immense research interest, while only a handful of

Received 25 February 2013

lncRNAs have been characterized thoroughly. Their involvement in the fundamental cellular processes

Received in revised form 31 May 2013

including regulate gene expression at epigenetics, transcription, and post-transcription highlighted a cen-

Accepted 1 June 2013

tral role in cell homeostasis. However, lncRNAs studies are still at a relatively early stage, their definition,

Available online 10 June 2013

conservation, functions, and action mechanisms remain fairly complicated. Here, we give a systematic

and comprehensive summary of the existing knowledge of lncRNAs in order to provide a better under-

Keywords:

standing of this new studying field. lncRNAs play important roles in brain development, neuron function

Expression signature

lncRNA and maintenance, and neurodegenerative diseases are becoming increasingly evident. In this review,

we also highlighted recent studies related lncRNAs in central nervous system (CNS) development and

Noncoding RNA

Neuron neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s

Neurodegenerative disease disease (HD) and amyotrophic lateral sclerosis (ALS), and elucidated some specific lncRNAs which may be

important for understanding the pathophysiology of neurodegenerative diseases, also have the potential

as therapeutic targets. © 2013 Elsevier Inc. All rights reserved.

Contents

1. Introduction ...... 70

2. Biology of lncRNAs ...... 70

2.1. Definition of lncRNAs...... 70

2.2. Evolution or conservation ...... 71

2.3. Function or transcription noise ...... 71

2.4. Stability ...... 71

Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; A␤42, amyloid-␤-42; A␤40, amyloid-␤-40; APP, amyloid precursor protein; BACE1, ␤-

site amyloid precursor protein-cleaving enzyme; BC200 (BCYRN1), brain cytoplasmic RNA 1; BC1, brain cytoplasmic RNA 1; BDNF, brain derived neurotrophic factor;



BRIC–Seq, 5 -bromo-uridine immunoprecipitation chase followed by deep sequencing; Camk2n1, calcium/calmodulin-dependent protein kinase II inhibitor 1; CaMKII,

2+

Ca /calmodulin-dependent protein kinase II; catRAPID, fast predictions of RNA and protein interactions and domains; CHIRP-Seq, chromatin isolation by RNA purification

followed by deep sequencing; CNS, central nervous system; c-KLAN, combined knockdown and localization analysis of noncoding RNAs; DJ-1 (PARK7), Parkinson disease

protein 7; eIF4A, eukaryotic initiation factor 4A; ENORs, expressed noncoding regions; FUS/TLS, fused in sarcoma/translated in liposarcoma; Gad1, glutamate decarboxylase

1; GDNFOS, glial cell derived neurotrophic factor opposite strand; HAR1, human accelerated regions 1; HGNCHOTAIRM1, HOX antisense intergenic RNA myeloid 1; HUGO,

Gene Nomenclature Committee; HD, Huntington’s disease; HTTAS, Huntingtin antisense; iPSC, induced pluripotent stem cells; ISH, in situ hybridization; lincRNAs, large

intergenic noncoding RNAs; lncRNAs, long noncoding RNAs; LTD, long-term depression; LTP, long-term potentiation; LRRK2, leucine-rich repeat kinase 2; Malat1, metastasis-

associated lung adenocarcinoma transcript 1; NAT-Rad18, natural antisense-Rad 18; ncRNAs, noncoding RNAs; Nkx2.2 AS, Nkx2.2 antisense; NO, Nitric oxide; NOSs, nitric

oxide synthases; Nrgn, neurogranin; NTAs, natural antisense RNAs; ORF, open reading frame; PCG, protein coding gene; PD, Parkinson’s disease; PINK1, phosphatase and

tensin homologue induced putative kinase 1; PRC2, polycomb repressive complex 2; REST/NRSF, RE1-silencing transcription factor/neuron-restrictive silencer factor; RIP-

Chip, RNP immunoprecipitation-microarray; RNCR2, retinal noncoding RNA 2; SAGE, serial analysis of gene expression; Shh, sonic hedgehog; Six3OS, Six3 opposite strand;

SOX2, SRY (sex determining region Y)-box 2; Sox2OT, Sox2 overlapping transcript; TDP43TAR, DNA-binding domain protein 43; TUG1, taurine upregulated gene 1; wtSOD1,

wilde type Cu/Zn superoxide dismutase; Xist, X-inactive specific transcript.

∗

Corresponding author. Tel.: +86 02061643500.

E-mail addresses: aiminji [email protected], [email protected] (A. Ji).

1

The authors contributed equally to this work and should each be considered co-first author.

0361-9230/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brainresbull.2013.06.001

70 P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80

2.5. lncRNA classification and subgroup ...... 71

2.6. How lncRNAs play function and the possible roles of lncRNAs...... 72

3. lncRNAs in the central nervous system ...... 72

3.1. lncRNAs in brain development ...... 72

3.2. LlncRNAs in neural differentiation and maintenance...... 73

3.3. lncRNAs in synaptic plasticity, cognitive function and memory ...... 74

3.4. lncRNAs in aged brain and neurodegenerative disorders...... 74

3.4.1. Dysregulated lncRNAs in Alzheimer’s disease ...... 76

3.4.2. Dysregulation of lncRNAs in Parkinson’s disease ...... 76

3.4.3. Dysregulation of lncRNAs in Huntington’s disease ...... 76

3.4.4. Dysregulation of lncRNAs in amyotrophic lateral sclerosis ...... 77

4. Perspective and challenge ...... 77

Acknowledgements ...... 77

References ...... 77

1. Introduction 2. Biology of lncRNAs

Over the last decade, advances in genome-wide analysis of 2.1. Definition of lncRNAs

the eukaryotic transcriptome have revealed that up to 90% of the

human genome are transcribed, however, GENCODE-annotated The initial lncRNAs, such as XIST (X-inactive specific tran-

exons of protein-coding genes only cover 2.94% the genome, while script) and H19 were first discovered by searching cDNA libraries

the remaining are transcribed as noncoding RNAs (ncRNAs) (ENC for clones in 1980s and 1990s (Brown et al., 1991; Bartolomei

Project and Consortium, 2012). Noncoding transcripts are further et al., 1991). With the improvement of microarray sensitivity and

divided into housekeeping ncRNAs and regulatory ncRNAs. House- sequencing technology, an abundance of lncRNAs transcripts have

keeping ncRNAs, which are usually considered constitutive, include been found (Kapranov et al., 2007). However, unlike miRNAs, as

ribosomal, transfer, small nuclear and small nucleolar RNAs. Reg- lacking of uniform systematic annotation systems cause the same

ulatory ncRNAs are generally divided into two classes based on lncRNAs with different names in science literatures, which increase

nucleotide length. Those less than 200 nucleotides are usually the difficulty to retrieve and integrate the study results.

referred to as short/small ncRNAs, including microRNAs (miRNAs), As the increasing acquaintance of lncRNAs, defining lncRNAs

small interfering RNAs and Piwi-associated RNAs, and those greater simply based on nucleotide size (>200 nt) and lack of capability

than 200 bases are known as long noncoding RNAs (lncRNAs) of protein-coding more than 100 amino acids is far from scientific

(Nagano and Fraser, 2011). in intellectually. First, the cutoff of 200 nucleotides is arbitrarily

The crucial role of miRNAs in post-transcriptional gene chosen limited by the current RNA purification protocols, taking no

regulation by repressing gene expression via targeting semi- consideration of the functional meaning (Kapranov et al., 2007). The

complementary motifs in target mRNAs has been highlighted (Lee second unreasonable is the protein-coding ability. As we know, the

et al., 1993). An abundance of studies showed the disrupted miRNAs Protein Coding Gene (PCG) is defined as a transcript that contains

in cancer (Liu et al., 2012), stroke (Wu et al., 2012), neurologi- an open reading frame (ORF) longer than 100 amino acids (Dinger

cal diseases (Bian and Sun, 2011), suggesting the miRNAs must et al., 2008a). However, studies have found lncRNAs can contain

play some roles in disease pathologic process, diagnosis, progno- ORFs longer than 100 amino acids but unnecessarily synthesize

sis, and also with the potential as promising treatment targets. to polypeptides, in addition, polypeptides shorter than 100 amino

lncRNAs have been attracting intense interest with the attractive acids can also be functional in organisms as peptide (Washietl et al.,

possibility to find new molecules and mechanisms that could shed 2011). Studies have demonstrated that the same RNA can be spliced

light on the explanation of organismal complexity and complex into different alterations play the PCGs functions or non-coding

diseases. functions (Candeias et al., 2008; Martick et al., 2008; Poliseno et al.,

The central nervous system (CNS) is the most highly evolved 2010). It is clear that the strict dichotomy between protein-coding

and sophisticated biological system. It is comprised of an enormous and non-coding transcripts is unadvisable.

array of neuron and glial cell subtypes which distributed at the Given the aforementioned limitations, one updated definition

strict and precise region, forming into dynamic neural networks describes lncRNAs as RNA molecules that may function as either

responding with internal signal and external stimulation, then primary or spliced transcripts and not belong to the known classes

responsible for mediating the complex functional repertoire of the of small RNAs in one category, and structural RNAs in the other

CNS including performing higher order cognitive and behavioral (Mercer et al., 2009). This definition implies the lncRNAs can have

(Graff and Mansuy, 2008). NcRNAs and their associated orches- either coding or noncoding characteristic, however, the definition

trated networks are highly adapted to the complex repertoire of immensely enlarges the number of lncRNAs, some RNAs which

neurobiological functions. lncRNAs, as one of the most abundant may not know so far are falsely classified as lncRNAs. The lat-

classes of ncRNAs, which transcribed from the different location est definition proposed by HUGO Gene Nomenclature Committee

of genome are highly expressed in brain (Ravasi et al., 2006; (HGNC) describes lncRNAs as spliced, capped, and polyadenylated

Mercer et al., 2008; Ponjavic et al., 2009). The roles of lncRNAs RNAs (Wright and Bruford, 2011). Nevertheless, as the existence of

in brain development, neuron function, maintenance, differenti- unspliced and/or non-polyadenylated lncRNAs (Nakaya et al., 2007;

ation and neurodegenerative diseases are becoming increasingly Kapranov et al., 2010; Yang et al., 2011), this definition is also not

evident. For the purpose of this review, we will firstly give a sys- completely true.

tematic and comprehensive profile of lncRNAs based on the existing Most of scholars tend to believe that there may be a strong

knowledge, and highlight their expression and function involved in possibility that the genome itself has no clear division between

CNS development, functional maintenance and neurodegenerative coding and noncoding transcripts, and that both are evolved to

disease. encode a continuous spectrum of transcripts and information

P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80 71

without our unnecessary arbitrary distinction (Dinger et al., observed, although the number is not known yet (Ponting et al.,

2008b). The strongest evidence comes from the bifunctional 2009). A study did find a form of transcriptional noise where the

lncRNA-SRA1, which was initially thought an RNA transcript that gene coupled to the transcription of another gene located within a

functions as a eukaryotic transcriptional coactivator for steroid radius of −100 kb along the mouse gene. This transcription is also

hormone receptors have now been found to encode an endogenous called the “rippling”, and refers to an induced expression irrespec-

protein (SRAP) (Lanz et al., 1999; Leygue, 2007). In order to avoid tive of whether transcription is initiated at a coding or noncoding

confusion, we need to stress that “large intergenic” noncoding locus (Ebisuya et al., 2008).

RNAs (lincRNAs) appeared in literature are an important subgroup Currently, what concerns us is how many lncRNAs are func-

of lncRNAs, which was also called “large interventing” (Guttman tional? This is tough to answer. Recently, the issue about how many

et al., 2009) or “large” RNAs (Huarte and Rinn, 2010). human genes are functional has caused heated debate by the recent

Currently, only very limited lncRNAs have been validated by slew of ENCyclopedia of DNA Elements (ENCODE) Consortium pub-

experiment, most of the lncRNAs included in various database are lications, specifically the article signed by all Consortium members,

annotated as lncRNAs via bioinformatics, they still need experiment put forward the idea that more than 80% of the human genome is

validations. functional (ENC Project and Consortium, 2012). A series of papers

have already commented critically on aspects of the ENCODE infer-

2.2. Evolution or conservation ences (Eddy, 2012; Niu and Jiang, 2013; Green and Ewing, 2013;

Graur et al., 2013). Identification the functional lncRNAs is another

Since vast numbers of lncRNAs have been discovered, evolution challenge for lncRNAs research, there still be a long way to go.

or conservation about lncRNAs attracted great attention (Okazaki

et al., 2002; Wang et al., 2004). As the formula of functional protein- 2.4. Stability

coding sequences is highly constrained, we have a preconception

that conservation provides an important evidence for lncRNA func- Stability is another consideration for lncRNAs functions. In

tion. Traditionally, constraint is estimated by the proportion of the our understanding, the half-life of each mRNA is closely related

nucleotide substitution rate in functional sequence, which can be to its physiological function, whether this principle can also be

divided into the three groups; neutral, unconstrained, and con- applied to lncRNAs need to be verified. One study using the

strained. Compared to PCGs and small ncRNAs, lncRNAs are weakly customized noncoding RNA array analyzed the half-life of ∼800

constrained at the primary sequence level. For PCGs, the average lncRNAs and ∼12,000 mRNAs in the mouse neuro-2a cell line, the

nucleotide substitution ratio is 10%, whereas for the lncRNAs, one results showed only a minority of lncRNAs were unstable. Mak-

study showed the ratio was 90–95% by analyzing the intergenic ing a comparison with mRNAs, lncRNAs have less half-life and

noncoding RNAs with 3122 average full-length, suggesting only variability over a wide range, suggesting lncRNAs have complex

5–10% sequence with conservation (Ponjavic and Ponting, 2007). A metabolism and widespread functionality. They further divided the

concrete example is the most intensely studied lncRNA-Xist, which lncRNAs into unstable (half-life < 2 h) and extreme stability (half-

is essential for X chromosome inactivation in female cells (Cawley life > 16 h) groups according to half-life, revealed that intergenic

et al., 2004), Xist shows very little sequence conservation through- and cis-antisense RNAs were more stable than those derived from

out the eutherian lineage (Plath et al., 2002). introns; and the spliced ones were more stable than unspliced (sin-

However, calculating the promoter sequences of mouse lincR- gle exon) transcripts; nuclear-localized lncRNAs were more likely

NAs and mRNAs yields very interesting results, lncRNA promoters to be unstable than other subcellular localization (Clark et al., 2012).



were on average more conserved than their exons, and almost as Another study surveyed the RNA half-life in HeLa cells by 5 -bromo-

conserved as protein-coding genes (Carninci et al., 2005; Guttman uridine immunoprecipitation chase followed by deep sequencing

et al., 2009; Derrien et al., 2012). Multi-disciplinary study the highly (BRIC–seq), the results indicated the long half-life RNAs (half-

conserved and brain-expressed mouse lincRNAs in bird and opos- life ≥ 4 h) accounted for a significant proportion of ncRNAs, as well

sum showed, in contrast to protein-coding genes, lincRNAs were as mRNAs involved in housekeeping functions, whereas the RNAs

highly variable at the sequences, transcriptional start sites, exon with a short half-life (half-life < 4 h) included the known regulatory

structures, and the lengths of these noncoding genes, however, ncRNAs and regulatory mRNAs. They also found that the stability

their putative promoter regions and across exon–intron bound- of a significant set of short-lived ncRNAs would be regulated by

aries, also the pattern of brain expression during embryonic and external stimuli, such as retinoic acid treatment (Tani et al., 2012).

early postnatal stages were pronounced evolutionary conservation Their findings in line with the proposed interpretation, which is

(Chodroff et al., 2010). the unstable ncRNAs can provide rapid response to external stimuli

Is lncRNAs conservation or not? If so, how they perform? We (Tani et al., 2012; Mercer et al., 2009).

may renovate our knowledge that judging the conservation of There are still some unexplained questions for lncRNAs stability

lncRNAs by the simple primary sequences; this is not eternally studies, like what determine their stabilities. Monitoring RNAs half-

invariable principle. lncRNAs may perform conservation in differ- life will provide a powerful tool for choosing the research targets

ent and various ways, including genomic locus, promoter regions for further investigation.

(Guttman et al., 2009; Chodroff et al., 2010), expression patterns

(Chodroff et al., 2010), second structures (Washietl et al., 2005) and 2.5. lncRNA classification and subgroup

splicing patterns (Ponjavic et al., 2007). It is possible that the func-

tional conservations but not the primary sequences are critical for lncRNAs can exceed 100,000 nucleotides and cover a wide range

their broad function in cell biology (Guttman and Rinn, 2012). of gene positions. Generally, according to their transcription pos-

itions of the genome, lncRNAs are categorized into three big groups:

2.3. Function or transcription noise transcribed relative to the host PCG, transcribed from the gene

regulator regions and some specific chromosomal regions, every

Given their abundance, much lower transcription level and group can be further subgrouped (Fig. 1). In addition, some lncRNAs

low sequence conservation, the functions of lncRNAs have ever exhibit mixed characteristics, such as marcoRNAs, which encom-

been questioned. Existing evidences have confirmed their broad pass huge genomic distances and multi-gene transcripts or even the

functions; however, we have to declare that not all lncRNAs are whole chromosome (Mercer et al., 2009). Intriguingly, mitochon-

functional. lncRNAs as transcriptional noise have indeed been drial lncRNAs have been identified by deep-sequencing analysis

72 P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80

Fig. 1. Schematic diagram illustrating the origin of lncRNAs. lncRNA are divided into three big groups. (I) Transcribe relative to the host PCG. (1) Sense or antisense RNAs

(when the lncRNA overlaps one or more exons of another transcript on the same or opposite strand respectively. The antisense also called natural antisense transcripts, NATs);

(2) bidirectional RNAs (when the expression of lncRNA and a neighboring coding transcript on the opposite strand is initiated in close genomic proximity); (3) intronic RNAs

(when the lncRNA is derived from an intron of a second transcript); and (4) intergenic RNAs (when the lncRNA is localized between two genes, also called large intergenic

 

RNAs, lincRNAs). (II) Transcribed from gene regulatory regions. (5) 3 -UTR associated RNAs (lncRNAs derived from 3 -untranslated regions of protein-coding transcript, also

named uaRNAs) (Mercer et al., 2011); (6) promoter associated RNAs (lncRNAs transcribed from promoter domains of protein-coding genes) (Hung et al., 2011); (7) enhancers

or enhancer-like lncRNAs (lncRNAs transcribed from enhancer domains and expressed coordinately with, activity-dependent genes, or lncRNAs exhibiting enhancer activity)

(Orom et al., 2010). (III) lncRNAs transcripted from the specific chromosomal regions. (8) Telomeres, telomeric repeat-containing RNA (referred to as TERRA) (Azzalin et al.,

2007).

and confirmed by Northern blotting and strand-specific qRT-PCR. RNA and protein interactions and domains (catRAPID) (Bellucci

The study also demonstrated that mitochondrial lncRNAs form et al., 2011), and combined knockdown and localization analysis

intermolecular duplexes and their expression profiles showed cell of noncoding RNAs (c-KLAN) (Chakraborty et al., 2012), these new

and tissue-specific, suggesting the functional role of mitochondrial technologies will be much helpful for us to understand these inter-

lncRNAs in mitochondrial gene expression regulation (Rackham actions and mechanisms of lncRNAs. The increasing knowledge in

et al., 2011). the field will significantly enrich the probability to describe the

Analyzing the genomic context of lncRNAs can help predict their spectrum of lncRNAs functions in the immediate future.

functional role, as their functions have close relationship with their

associated protein-coding genes, which may serve as a guideline for

3. lncRNAs in the central nervous system

further function and mechanism studies.

The primate nervous system is most elaborate in biological

system. Understanding their molecular mechanisms is a big chal-

2.6. How lncRNAs play function and the possible roles of lncRNAs

lenge and a subject interest among a lot of scientists. Noncoding

sequences associated with human neural genes exhibit prominent

lncRNAs have broad spectrum of functions involved in almost

signatures of positive selection and accelerated evolution, which

every aspect of the biological process, from chromatin structure to

provide new avenues to link genetic and phenotypic changes in the

the protein level. Although the full functions of lncRNAs are not yet

evolution of the human brain. The flexible and complex functions of

clearly defined, the paradigms of how lncRNAs function have been

lncRNAs coincides with the diversity and elaborate nature of CNS,

well summarized by Wilusz et al. (2009) (Fig. 2). Their possible

making lncRNAs as ideal candidates to explain the rapid evolution

roles in cell physiology are described as: (I) signals for integrat-

of human CNS or as promising breakthrough for insight into the

ing temporal, spatial, developmental and stimulus-specific cellular

molecular mechanisms of CNS development and neuropsychiatric

information; (II) decoys with the ability to sequester a range of

diseases (Mattick, 2007; St and Wahlestedt, 2007). Whereas most

RNA and protein molecules, thereby inhibiting their functions; (III)

studies focus on miRNAs (Fiore et al., 2011), recent studies have also

guides for genomic site-specific and more widespread recruitment

begun to define neurobiological roles of lncRNAs in CNS (Ponjavic

of transcriptional and epigenetic regulatory factors; (IV) scaffolds

et al., 2009; Mercer et al., 2008; Belgard et al., 2011).

for macromolecular assemblies with varied functions. The spe-

cific functions of a single lncRNA may belong to any or combined

roles which are determined by many elements, such as the tissue- 3.1. lncRNAs in brain development

specific, and the physiological status of cells (Mercer et al., 2009;

Da et al., 2012). Comparison the human genome with our closest relative, the

lncRNAs as a bimolecular play the function role by interacting chimpanzee, discovered a ranking of regions in the human genome

with other three kinds of biomolecules-DNA, RNA and protein, demonstrated significantly evolutionary acceleration. HAR1, one of

forming binary even ternary interaction complex. Seeking the inter- the most dramatic “human accelerated regions” belongs to a part

ference targets from their interactions will be more beneficial of an overlapping lncRNA gene, HAR1F (HAR1A). The study showed

to drug discovery (Bhartiya et al., 2012). With the application of HAR1F specifically expressed in Cajal-Retzius neurons in the devel-

advanced technology, RNP immunoprecipitation-microarray (RIP- oping human neocortex from 7 to 19 gestational weeks, a crucial

Chip), Chromatin Isolation by RNA Purification followed by deep period for cortical neuron specification and migration. In addition,

sequencing (CHIRP-Seq) (Chu et al., 2011), Fast predictions of HAR1A expression correlated with reelin, suggesting it similarly

P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80 73

Fig. 2. Paradigms for how lncRNAs function. Recent studies have identified a variety of regulatory paradigms for lncRNAs function, which are highlighted here. (I) Trans-

criptional interference: induce chromatin remodeling and histone modification (1). (II) Gene post-transcription regulation. lncRNAs hybridize to the mRNAs by base-pairing

with the complementary sequence to blocked the splice sites of spliceosome, thus resulting in alternatively spliced transcripts (2), or translation inhibition (3), or mRNA

degeneration (4). lncRNAs allow Dicer to generate endogenous siRNAs (5). (III) Interaction with other biological molecules. Interact with proteins, modulate the activity of

the protein by binding to specific protein partners (6), or alter the protein location in the targets position (7), serve as a scaffold to allows the forming of larger RNA–protein

complex (8); interact with miRNAs to sponge the function of miRNAs (9).

coordinates the establishment of regional forebrain organization Disrupting the specific lncRNAs by gene knockout or over

(Pollard et al., 2006). expression will allow us to gain more knowledge in this field.

Allen Brain Atlas (ABA) is a large-scale gene expression

study of the adult mouse brain through high-throughput RNA 3.2. LlncRNAs in neural differentiation and maintenance

in situ hybridization to visualize the expression of over 20,000

transcripts at cellular resolution, which over 1000 probes tar- lncRNAs play the functions in mediating neural development

geted against noncoding transcripts originating from intergenic, and differentiation programs, including neural line restriction, cell

intronic, and antisense regions (Lein et al., 2007). Utilizing the fate determination and progressive stage differentiation. In the

data for further analysis found 849 ncRNAs (of 1328 examined) early stages, lncRNA-AK053922 which transcribed from the Gli3

expressed in the adult mouse brain, majorities were associated locus has shown the ability to help specify distinct neuronal cell

with specific neuroanatomical regions, cell types, or subcellular types though acting as a bifunctional transcriptional switch which

compartments (Mercer et al., 2008). This study provides com- can either repress or activate sonic hedgehog (Shh) signaling

pelling evidence that many of these transcripts are intrinsically (Meyer and Roelink, 2003; Hashimoto-Torii et al., 2003). Study-

functional. ing the mouse retinal development by a serial analysis of gene

MacroRNAs as a novel subset of lncRNAs are believed to be expression (SAGE) at multiple time points revealed multiple evolu-

served as precursors of other small and lncRNA transcripts. Sixty- tionary conserved lncRNA transcripts dynamically and specifically

six regions have been identified as macroRNA candidates in mouse expressed in developing and mature retinal cell types, suggest-

genome, each of which maps outside known protein-coding loci ing these lncRNAs are functional in neuron development and

and have a mean length of 92 kb. In these expressed noncoding physiology. Another study using chromatin-state maps identified

regions (ENORs), the ENOR28 and ENOR31 with the capacity to give approximately 1600 large multi-exonic RNAs expressed across four

rise to multiple macroRNAs, and both exhibited preferential enrich- mouse cell types, and further independently validated over 100

ment within the nervous system (Furuno et al., 2006). Although the lincRNAs by cell-base assays, the results indicated that expressed

specific function of ENOR28 and ENOR31 are not known yet, know- lincRNAs played diverse roles in the process from embryonic stem

ing exactly which groups of neurons in the brain express ENOR28 cell pluripotency to cell proliferation, implying these lncRNAs have

and ENOR31 transcripts will provide indirect information as to their diverse biological processes (Guttman et al., 2009). Analysis of the

functions. 169 lncRNAs which dynamically expressed at one or more devel-

These evidences indicate that lncRNAs play an important role opmental stages during neural stem cell-mediated fate restriction

in brain development. However, more direct evidence is needed. found these lncRNAs co-expressed with the protein coding genes

74 P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80

which are critical in neural development, suggesting lncRNAs as a retrograde neurotransmitter and hence is likely to be important

and protein coding genes share regulatory mechanisms and in learning, long-term potentiation (LTP) and long-term depression

lncRNAs are integrated into complex environmentally mediated (LTD) (Muller, 1996). Nitric oxide synthases (NOSs) are a family

neural and glial developmental gene expression programs (Mercer of enzymes that catalyze the production of NO from l-arginine.

et al., 2010). RNA-Seq analysis human neurons derived from Studies of the Lymnaea stagnalis snail found that an antisense RNA

induced pluripotent stem cells (iPSC) found a series of lncRNAs which is complement to the NOS-encoding mRNA are transcribed

dramatically changed during the transition from iPSC to early dif- from a kind of NOSs pseudogene, bringing down the NOS pseudo-

ferentiated neurons, one of them is lncRNA-HOTAIRM1, a regulator gene antisense transcript caused the upregulation of NOS mRNA

of several HOXA genes during myelopoiesis, which was observed transiently, and the timeline coincided with the critical window

up-regulated in differentiated neurons (Lin et al., 2011). RNCR2 for memory formation, implying the antisense NOS pseudogene

also known as Gomafu and Miat which expressed and located in transcripts associate with memory formation by modulating the

neuron nucleus regulates the retinal cell fate specification (Sone expression of NOSs mRNAs (Korneev et al., 1999, 2005; Kemenes

et al., 2007; Rapicavoli et al., 2010). Study the expression profile of et al., 2002).

human embryonic stem cells using a custom-designed microarray The rodent-specific BC1 and the non-homologous primate-

and identify the lncRNAs required for neurogenesis found RMST specific BC200 lncRNA are thought to operate as modulators of

(AK056164, AF429305 and AF429306), lncRNA N1 (AK124684), local protein synthesis in postsynaptic dendritic microdomains, in

lncRNA N2 (AK091713) and lncRNA N3 (AK055040) were required a capacity in which they contribute to the maintenance of long-

for efficient neuronal differentiation (Ng et al., 2012). term synaptic plasticity (Muddashetty et al., 2002). Further study

Natural antisense RNAs (NTAs) account for a large number of revealed that BC1 selectively targeted eukaryotic initiation fac-

lncRNAs, which modulate the expression of sense transcripts or tor 4A (eIF4A), an ATP-dependent RNA helicase to mediate the

influence sense mRNA processing. NATs are particularly prevalent translation repression at the level of initiation (Wang et al., 2002;

in the CNS and have been postulated to regulate important neuronal Lin et al., 2008). Neurogranin (Nrgn) and calcium/calmodulin-

processes (Werner and Sayer, 2009). Nkx2.2 antisense (Nkx2.2 AS) dependent protein kinase II inhibitor 1 (Camk2n1, CaMKIINalpha)

which transcribed from the antisense of Nkx2.2 gene with the func- are highly expressed proteins in mouse brains and play an impor-

tion of regulating transcription level of Nkx2.2 (a transcription tant role in synaptic long-term potentiation via regulation of

2+

factor) by cis, over expressed Nkx2.2 AS induced modest increase Ca /calmodulin-dependent protein kinase II (CaMKII) (Gerendasy

of Nkx2.2 mRNA level, suggesting Nkx2.2 upregulation induced and Sutcliffe, 1997; Kennedy, 1998; Lisman et al., 2002), Camk2n1

oligodendrocytic differentiation is the minor result of Nkx2.2AS also play a physiological role in controlling CaMKII activity from

overexpression (Tochitani and Hayashizaki, 2008). Six3 opposite an early stage of memory consolidation (Lepicard et al., 2006).

strand (Six3OS) is transcribed from the distal promoter region of the Multiple overlapping transcripts transcribed from both the sense

opposite strand of gene encoding the homeodomain transcription and antisense of the gene locus of these 2 proteins co-transcribe,

factor Six3. Study developing retinas showed that Six3OS regulated increase the diversity of posttranscriptional regulation of their gene

Six3 activity by acting as a molecular scaffold to recruit histone products during cerebral corticogenesis and synapse function (Ling

modification enzymes to Six3 target gene, not modulating Six3 et al., 2011). Brain derived neurotrophic factor (BDNF) belong to

expression itself, then played an essential role in regulating retinal a class of secreted growth factors that are essential for suppor-

cell specification (Rapicavoli et al., 2011). ting neuronal growth, survival, synaptic plasticity and involves in

These researches provide just the “tip of the iceberg” of the learning and memory process (Figurov et al., 1996; Kang and Schu-

complex interrelationships between lncRNAs and neurons. The man, 1995; Yamada et al., 2002). Dissecting the human BDNF

increasing in research interest must reveal the roles of lncRNA in locus found the antiBDNF (BDNF-AS, also annotated as BDNF-OS)

neuron. which transcribed from the antisense of BDNF gene, formed dsRNA

duplexes with BDNF mRNA in the brain. Losing function of BDNF-

3.3. lncRNAs in synaptic plasticity, cognitive function and AS by antagoNAT in vivo or siRNA in vitro both resulted in increased

memory BDNF mRNA and protein level, then promoted the neurite out-

growth and maturation, suggesting antiBDNF play a role in BDNF

Emerging studies have shown that lncRNAs play a direct role function (Modarresi et al., 2012; Lipovich et al., 2012). Further study

in gene regulations involved in synaptic plasticity, cognitive func- found BDNF-AS inhibited the BDNF transcription by recruiting of

tion and memory. The normal development of GABAergic inhibitory the enhancer of zeste homolog 2 (EZH2) and polycomb repressive

interneurons in the hippocampus is responsible for learning in complex 2 (PRC2) to the BDNF promoter region (Pruunsild et al.,

the embryonic and adult brain. Evf-2 lincRNA which transcribed 2007; Modarresi et al., 2012).

from the Dlx-5/6 ultraconserved region is essential for GABAergic These observations suggest that lncRNAs might orchestrate the

neuron development. Evf-2 play the function via Dlx-2 trans- fidelity of synaptic plasticity, congnitive and memory process by

criptional coactivator to increase the transcriptional activity of dynamically monitoring and integrating multiple transcriptional

Dlx-5/6 and the glutamate decarboxylase 1 (Gad1, necessary for and post-transcriptional events.

the conversion of glutamate to GABA) (Feng et al., 2006), and

then regulates the gene expression of GABAergic interneurons

in the developing mouse brain. Evf-2 silence results anomalies 3.4. lncRNAs in aged brain and neurodegenerative disorders

synaptic activity in mice by the aberrant formation of GABAergic

circuitry in the hippocampus and dentate gyrus (Bond et al., 2009). lncRNAs have broad spectrum functions in the normal brain

Metastasis-associated lung adenocarcinoma transcript 1 (Malat1) development and function maintenance, thus, not surprisingly

is expressed in numerous tissues and highly abundant in neurons, that lncRNAs are disrupted in aged brain and CNS disorders. A

while knock-down of Malat1 decreases synaptic density, whereas study quantified the levels of nearly 6000 lncRNAs in 36 surgically

its over-expression results in a cell-autonomous increase in synap- resected human neocortical samples (primarily derived from

togenesis (Bernard et al., 2010). tem-poral cortex) spanning infancy to adulthood indentified

lncRNAs are also implicated in promoting long-term changes in the 8 ncRNA genes with distinct developmental expression pat-

synaptic strength. Nitric oxide (NO) is cellular signaling molecule, terns (Lipovich et al., 2013). There are also increasing studies have

playing a vital role in many biological processes, including function shown that lncRNAs are associated with several neurodegenerative

P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80 75

Table 1

Dysregulated lncRNAs in neurodegenerative diseases.

lncRNAs Description Disease associated Down or up Biological function References

Sox2OT As a biomarker of AD and PD Up Regulate Arisi et al. (2011)

neurodegeneration co-transcribed Sox2

gene expression to

down neurogenesis

1810014B01Rik Sever as the biomarker AD and PD Up The function of Arisi et al. (2011)

of neurodegeneration 1810014B01Rik is not

known yet

BC200 Homologous with AD and PD Soma: Up Modulate local Mus et al. (2007)

rodent BC1 lncRNA, the Dendritic: Down proteins in

earliest specific postsynaptic dendritic

example showed microdomains to

lncRNAs conservation maintenance of

long-term synaptic

plasticity

BACE1-AS Transcribe from the AD Up Increase BACE1 mRNA Faghihi et al. (2008)

antisense stability resulting

protein-coding BACE 1 additional A␤42

gene generation through a post-transcriptional feed-forward

mechanism

NAT-Rad18 Transcribed from the AD Up Down the expression Parenti et al. (2007)

antisense of protein of DNA repair protein

coding gene Rad18 Rad18 resulting the

neuron more sensitive

to apoptosis

17A Embedded in the AD Up Impair GABAB Massone et al. (2011)

human signaling pathway by

G-protein-coupled decreasing GABAB R2

receptor 51 gene transcription

GDNFOS Transcribed from the AD Dysregulated/differences Modulate the Airavaara et al. (2011)

opposite strand of in tissue expression expression of

GDNF gene only in patterns endogenous GDNF in

primate genomes, with human brain

different isoforms.

naPINK1 Transcribed from the PD Up Stabilize the Sai et al. (2012); Morais

antisense of PINK1 svPINK1resulting et al. (2009); Scheele

locus disturbed et al. (2007); Chiba

mitochondrial et al. (2009)

respiratory chain, and

then increase the

sensitivity to apoptosis

HAR1F Overlap the gene of HD and other Down Aberrant Zuccato et al. (2003);

HAR1, which shows neurodegenerative nuclear-cytoplasmic Shimojo (2008);

significant disease REST/NRSF trafficking Johnson et al. (2010);

evolutionary caused by mutated Seong et al. (2010)

acceleration in human huntingtin resulting

compared with the aberrant

chimpanzee expression of HAR1in

striatum

HTTAS Transcribed from the HD Down HTTAS v1 specifically Chung et al. (2011)

natural antisense reduces endogenous

transcript of the HD HTT transcript levels

repeat locus that

contain the repeat tract

DGCR5 DiGeorge syndrome HD Down DGCR5 is downstream Johnson et al. (2009)

critical region gene 5 target of REST in HD

(non-protein coding), disease

located on

chromosome 22q11

NEAT1 Nuclear enriched HD Up NEAT1 is essential for Johnson (2012)

abundant transcript the integrity of the

nuclear paraspeckle

substructure.

TUG1 TUG1 is expressed in HD Up Necessary for retinal Johnson (2012)

the retina and in the development, the

brain function with HD not

be mentioned.

Abbreviations: AD, Alzheimer’s disease; PD, Parkinson’s disease; HD, Huntington’s disease; Sox2OT, Sox2 overlapping transcript; BACE1-AS, ␤-site amyloid precursor protein-

cleaving enzyme 1 anti-sense; PINK1, phosphatase and tensin homologue induced putative kinase 1; GDNFOS, glial cell derived neurotrophic factor opposite strand; HAR1,

human accelerated region 1; REST/NRSF, RE1-silencing transcription factor/neuron-restrictive silencer factor; PRC2, polycomb repressive complex; TUG1, taurine upregulated gene.

76 P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80

disorders characterized by impaired cognitive function. We made significantly impairs GABAB signaling pathway. Inflammation

a summary on functional lncRNAs involved in this field (Table 1). in AD brain can trigger the 17A expression, then enhance the

secretion of A␤ and increase the A␤42/A␤40 peptide ratio to

3.4.1. Dysregulated lncRNAs in Alzheimer’s disease aggravate the disease (Massone et al., 2011).

Alzheimer’s disease (AD) is the most common neurodegenera- GDNFOS is transcribed from the opposite strand of GDNF gene

tive disorder. A neuropathological hallmark of AD is characterized only in primate genomes. Study has found GDNFOS isoforms differ-

by the progressive loss of synapses and, subsequently, neurons entially expressed in AD brains, further study may further reveal its

themselves, which occurs within diverse cortical circuits, begin- roles in human brain diseases (Airavaara et al., 2011). BDNF expres-

ning in the entorhinal cortex and the hippocampus (Braak and sion levels are impaired in neurodegenerative (Laske et al., 2011;

Braak, 1991; Kordower et al., 2001; Mucke et al., 1994). The patho- Zeng et al., 2010; Frade and Lopez-Sanchez, 2010), psychiatric and

logic process of AD is not well understood to date. One of the neurodevelopmental disorders (Luo et al., 2010; Gonul et al., 2011;

main reasons is the amyloid plaques deriving from the ␤-site amy- Dell’Osso et al., 2010). Upregulation neurotrophins is believed to

loid precursor protein-cleaving enzyme (BACE1) cleaved amyloid have beneficial effects on several neurological disorders. BDNF-AS

precursor protein (APP) aggregate on the neurons. In the normal inhibition provides a good strategy for specifically increasing BDNF

condition, the ratio of amyloid-␤-42 (A␤42)/amyloid-␤-40 (A␤40) level in vivo, which holds great therapeutic promise.

is balanced, while in AD brain, the shift resulting in increased levels These studies highlight the lncRNA-based regulatory pathways

of A␤42 level which is thought to cause the amyloid plaques (Minati associated with brain physiology and/or pathology.

et al., 2009; Ballard et al., 2011). A series of aberrant lncRNAs have

been found in the pathologic process of AD. 3.4.2. Dysregulation of lncRNAs in Parkinson’s disease

Sox2 overlapping transcript (Sox2OT) holds within one of its Parkinson’s disease (PD) is a chronic, progressive movement

introns the single-exon Sox2 gene, and shares the same transcrip- disorder, belongs to a group of conditions called motor system dis-

tional orientation (Fantes et al., 2003). Sox2OT is a stable transcript orders, which is caused by the loss of dopamine-producing cells

in mouse embryonic stem cells and embryoid body differentiation, in the brain. Despite many years of focus research, the reasons

also dynamically regulated during chicken and zebrafish embryo- have not yet been elucidated. Genetic research find the PD-familial

genesis (Mercer et al., 2008; Amaral et al., 2009). Interestingly, an related genes, such as alpha-synuclein, Parkin, PINK1 (phosphatase

unbiased study analyzed the microarray expression dataset of anti- and tensin homologue induced putative kinase 1), DJ-1 (also known

NGF AD11 transgenic mouse model by Logic Mining method found as Parkinson disease protein 7, PARK7) and LRRK2 (leucine-rich

Sox2OT and 1810014B01Rik would serve as the best biomarkers of repeat kinase 2), all these genes are associated with mitochondria

neurodegeneration in both early and late stages, however, nothing function, suggesting the homeostasis properties of mitochondria

is yet known about 1810014B01Rik (Arisi et al., 2011). are particularly important for PD (Sai et al., 2012). PINK1 gene

The primate BC200 in synapse plasticity has been validated by can be transactivated by the tumor suppressor PTEN (phosphatase

previous studies (Wang et al., 2002; Lin et al., 2008). BC200 has and tensin homolog), loss or overexpression of PINK1 implicates

been found declined in the frontal cortex of normal aging brain, but abnormal mitochondrial morphology, impaired dopamine release

increased in the AD patients, and the severity was parallel with the and motor deficits (Morais et al., 2009). naPINK1 is a human spe-

increased level of BC200 (Mus et al., 2007). However, another study cific noncoding RNA transcribed from the antisense of PINK1 locus,

showed the opposite results, compared with the normal brains, and with the ability of stabilizing the expression of svPINK1 (PINK1

BC200 RNA showed a 70% reduction in AD afflicted brains (Lukiw splice variant, with homologous C-terminus regulatory domain of

et al., 1992). The possible scenarios to explain the difference may be PINK1). naPINK1 silence results in the decreasing of svPINK1 in

caused by different sampling location of brain or the severity of dis- neurons, suggesting naPINK1 and svPINK1 are concordantly reg-

ease. Whether the BC200 is increased or decreased in AD brain, the ulated during mitochondrial biogenesis (Scheele et al., 2007). Mice

aberrant expression of BC200 is unquestionable, what the specific brains studies also achieved the similar results, the naPINK1 stable

function and mechanism will be reveled in the near future. the PINK1 expression may by dsRNA-mediated mechanism (Chiba

BACE1-AS which transcribed from the antisense protein-coding et al., 2009). These studies point to a broader genomic strategy for

BACE 1 gene is highly expressed in AD patients (Faghihi et al., treating the PD through regulation the PINK1 locus.

2008). Unlike the other NATs forming the duplex complex with

the sense of coding mRNA to inhibit mRNA translation, BACE1-AS 3.4.3. Dysregulation of lncRNAs in Huntington’s disease

play the function by increasing BACE1 mRNA stability then gener- Huntington’s disease (HD) is caused by an expansion of

ating additional A␤42 through a post-transcriptional feed-forward a CAG triplet repeat stretch within the Huntingtin gene. The

mechanism, implying that BACE1-AS may drive AD-associated expansion results in a mutant form of the huntingtin protein.

pathology, directly implicate in the increased abundance of A␤42 Huntingtin has been reported to regulate the nuclear transloca-

in AD (Faghihi et al., 2008). tion of the transcriptional repressor RE1-silencing transcription

Rad18 is an enzyme positively involved in the DNA damage factor/neuron-restrictive silencer factor (REST/NRSF), the mutated

repair system, NAT-Rad18 transcribed from the antisense of Rad18 huntingtin promoted aberrant nuclear-cytoplasmic trafficking of

gene. Microarray analysis the gene expression of A␤ stimulated REST/NRSF, then led to the disrupted expression of REST target

cortical neurons found that the NAT-Rad18 was up regulated genes including both protein coding genes and noncoding genes

then down regulated the post-transcription of Rad18, suggesting (Zuccato et al., 2003; Shimojo, 2008). To discover the ncRNAs

NAT-Rad18 reduce the ability of neuron suffering DNA damage involved in HD, a study characterized the ncRNAs expression pro-

stress, increasing their apoptosis susceptibility (Parenti et al., 2007). file of human HD brain tissues, found the expression of HAR1 was

Although no other report validated the increasing or decreasing significantly decreased in the striatum. The study also demon-

expression of NAT-Rad18 would aggravate or alleviate AD respec- strated that REST was targeted to HAR1 locus by specific DNA

tively, this finding has shown the potential role of NAT-Rad18 in regulatory motifs, resulting in potent transcriptional repression

the DNA damage repair system in AD. (Johnson et al., 2010). Huntingtin is thought to be a predominant

17A is a novel ncRNA embedded in the human G-protein- HEAT repeat alpha-solenoid, its domain structure and potential can

coupled receptor 51 gene (GPR51, GABA B2 receptor), playing its intersect with epigenetic silencer polycomb repressive complex

role by tightly controlling the alternative splicing of GPR51 to 2 (PRC2), a subset of lncRNAs bind to PRC2 to mediate the final

decrease transcription of the canonical form of GABAB R2, then common pathway for transcriptional dysregulation, thus, not only

P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80 77

neurodegeneration in HD, but also other neurodegenerative dis- sequencing (CHIRP-Seq) (Chu et al., 2011), Fast predictions of RNA

eases (Seong et al., 2010). Huntingtin antisense (HTTAS) is a natural and protein interactions and domains (catRAPID) (Bellucci et al.,

antisense transcript at the HD repeat locus that contains the repeat 2011), Combined knockdown and localization analysis of noncod-

tract. HTTAS v1 (exons 1 and 3) are reduced in human HD frontal ing RNAs (c-KLAN) (Chakraborty et al., 2012) make a tremendous

cortex. In cell systems, overexpression of HTTAS v1 specifically improvement for research. However, the problem is the identifica-

reduces endogenous HTT transcript levels, while siRNA knock- tion of regions of the genome where different cell types from the

down of HTTAS v1 increases HTT transcript levels. These findings same organism exhibit different patterns of histone enrichment.

provide strong evidence for the existence of a gene antisense to HTT, This problem turns out to be surprisingly difficult, even in simple

with properties that include regulation of HTT expression (Chung pairwise comparisons, because of the significant level of noise

et al., 2011). Reanalysis of the Affymetrix U133A and B microarray in ChIP-seq data. The second challenge is in the identification of

data on normal and HD brains found TUG1 (taurine upregulated the function of specific lncRNA both in bioinformatics approaches

gene, necessary for retinal development) is upregulated in HD brain and in hypothesis-driven experiments. Several bioinformatics

(Johnson, 2012). resources are available to researchers for different purpose and

they include database and repositories, annotation tool and other

software, for instance, NONCODE (http://www.noncode.org),

3.4.4. Dysregulation of lncRNAs in amyotrophic lateral sclerosis

fRNAdb (http://www.Ncrna.org/frnadb), lncRNAdb (http://

Amyotrophic lateral sclerosis (ALS) is an incurable neurode-

www.lncrnadb.org), Human Body Map lincRNAs (http://www.

generative disease characterized by progressive paralysis of the

Broadinstitute.org/genome bio/human lincrnas) etc. The develop-

muscles of the limbs, speech and swallowing, and respiration due

ment of transgenetic animal models and altering the expression

to the progressive degeneration of voluntary motor neurons. Mito-

level of special lncRNAs by down expression or over expression

chondrial dysfunction is steadily recognized as a central matter in

are formulary strategies to be used in experiment.

the pathogenesis of ALS (Cozzolino et al., 2012). TAR DNA-binding

In addition, molecules based on further elucidating how ncRNAs

domain protein 43 (TDP43) and fused in sarcoma/translated in

operate at the molecular, cellular and more hierarchical neural net-

liposarcoma (FUS/TLS) are RNA-binding protein (RBP) with a major

work levels remains elusive. Getting more understanding of these

nuclear localization, play the role in regulating different aspects of

will conceivably provide new venues for early diagnosis and treat-

RNA metabolism, including pre-mRNA splicing, which have pro-

ment of diseases.

found function in gene transcription. Study indicated the aberrant

accumulation of FUS/TLS and TDP43 in cytosolic directly kindles

Acknowledgements

wtSOD1 (wild type Cu/Zn superoxide dismutase) misfolding in

non-SOD1 FALS (familial ALS) and SALS (sporadic ALS), implying

Authors acknowledge the support given by the Joint Project

a shared pathogenic pathway in the molecular pathogenesis of ALS

of the Chinese Academy of Sciences and the Guangdong Province

(Pokrishevsky et al., 2012). Although there is no direct study detec-

Guangdong Science and Technology Plan Project (Project No.

ting the aberrant lncRNAs in ALS patient or experiment ALS model,

2009B091300129); and the Science and Technology Development

one previous study found the FUS/TLS was recruited by an lncRNA

project of Guangzhou (Project No. 2010UI-E00531-7).

to the genomic locus encoding cyclin D1, where the cyclin D1 tran-

scription is repressed in response to DNA damage signals, result

References

in increasing apoptosis tolerance of cells, suggesting the disrupted

FUS/TLS induced aberrant lncRNAs single may play a role in the

Airavaara, M., Pletnikova, O., Doyle, M.E., Zhang, Y.E., Troncoso, J.C., Liu, Q.R., 2011.

pathological changes of neurodegenerative diseases (Wang et al., Identification of novel GDNF isoforms and cis-antisense GDNFOS gene and their

regulation in human middle temporal gyrus of Alzheimer disease. Journal of

2008; Doi et al., 2008). These observations may set up a link indi-

Biological Chemistry 286, 45093–45102.

rectly showing that lncRNAs are at least partly responsible in ALS

Amaral, P.P., Neyt, C., Wilkins, S.J., Askarian-Amiri, M.E., Sunkin, S.M., Perkins, A.C.,

and other neurodegenerative diseases pathology processes. Mattick, J.S., 2009. Complex architecture and regulated expression of the Sox2ot

Finally, as the research is just starting to emerge on neurode- locus during vertebrate development. RNA 15, 2013–2027.

Arisi, I., D’Onofrio, M., Brandi, R., Felsani, A., Capsoni, S., Drovandi, G., Felici, G.,

generative diseases, this review provides only a summary of the

Weitschek, E., Bertolazzi, P., Cattaneo, A., 2011. Gene expression biomarkers in

intensively studied subjects. Neurodegenerative diseases belong

the brain of a mouse model for Alzheimer’s disease: mining of microarray data

to a large class of diseases, with a common pathological presence by logic classification and feature selection. Journal of Alzheimer’s Disease 24,

721–738.

to some extent. We dare to speculate that some specific lncRNAs

Azzalin, C.M., Reichenbach, P., Khoriauli, L., Giulotto, E., Lingner, J., 2007. Telomeric

may prove to have a common role in the pathological process and

repeat containing RNA and RNA surveillance factors at mammalian chromosome

that targeting these lncRNAs may be able to delay or even stop the ends. Science 318, 798–801.

Belgard, T.G., Marques, A.C., Oliver, P.L., Abaan, H.O., Sirey, T.M., Hoerder-

disease process.

Suabedissen, A., Garcia-Moreno, F., Molnar, Z., Margulies, E.H., Ponting, C.P.,

2011. A transcriptomic atlas of mouse neocortical layers. Neuron 71, 605–616.

Ballard, C., Gauthier, S., Corbett, A., Brayne, C., Aarsland, D., Jones, E., 2011.

4. Perspective and challenge

Alzheimer’s disease. Lancet 377, 1019–1031.

Bartolomei, M.S., Zemel, S., Tilghman, S.M., 1991. Parental imprinting of the mouse

H19 gene. Nature 351, 153–155.

The landscape of current knowledge on lncRNAs has consider-

Bellucci, M., Agostini, F., Masin, M., Tartaglia, G.G., 2011. Predicting protein associa-

ably changed over the last few years, and will likely continue to

tions with long noncoding RNAs. Nature Methods 8, 444–445.

change substantially in the coming years. It is obviously clear that Bernard, D., Prasanth, K.V., Tripathi, V., Colasse, S., Nakamura, T., Xuan, Z., Zhang,

M.Q., Sedel, F., Jourdren, L., Coulpier, F., et al., 2010. A long nuclear-retained non-

lncRNAs have numerous molecular functions, including epigenetic

coding RNA regulates synaptogenesis by modulating gene expression. EMBO

modification, translation and post-translation. Their complexity

Journal 29, 3082–3093.

supports the proposition that evolutionary innovations and expan- Bhartiya, D., Kapoor, S., Jalali, S., Sati, S., Kaushik, K., Sachidanandan, C., Sivasubbu,

sion of regulatory RNAs are fundamental reasons for the organic S., Scaria, V., 2012. Conceptual approaches for lncRNA drug discovery and future

strategies. Expert Opinion on Drug Discovery 7, 503–513.

complexity of eukaryotes.

Bian, S., Sun, T., 2011. Functions of noncoding RNAs in neural development and

There are still some challenges in our understanding of

neurological diseases. Molecular Neurobiology 44, 359–373.

lncRNAs. One important challenge is the technique used in iden- Bond, A.M., Vangompel, M.J., Sametsky, E.A., Clark, M.F., Savage, J.C., Disterhoft, J.F.,

Kohtz, J.D., 2009. Balanced gene regulation by an embryonic brain ncRNA is crit-

tifying the function lncRNAs exert in the pathological effects.

ical for adult hippocampal GABA circuitry. Nature Neuroscience 12, 1020–1027.

RNP immunoprecipitation-microarray (RIP-Chip) (Zhao et al.,

Braak, H., Braak, E., 1991. Neuropathological staging of Alzheimer-related changes.

2010), Chromatin Isolation by RNA Purification followed by deep Acta Neuropathologica 82, 239–259.

78 P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80

Brown, C.J., Ballabio, A., Rupert, J.L., Lafreniere, R.G., Grompe, M., Tonlorenzi, R., Gerendasy, D.D., Sutcliffe, J.G., 1997. RC3/neurogranin, a postsynaptic calpacitin for

Willard, H.F., 1991. A gene from the region of the human X inactivation centre setting the response threshold to calcium influxes. Molecular Neurobiology 15,

is expressed exclusively from the inactive X chromosome. Nature 349, 38–44. 131–163.

Candeias, M.M., Malbert-Colas, L., Powell, D.J., Daskalogianni, C., Maslon, M.M., Naski, Gonul, A.S., Kitis, O., Eker, M.C., Eker, O.D., Ozan, E., Coburn, K., 2011. Association

N., Bourougaa, K., Calvo, F., Fahraeus, R., 2008. P53 mRNA controls p53 activity of the brain-derived neurotrophic factor Val66Met polymorphism with hip-

by managing Mdm2 functions. Nature Cell Biology 10, 1098–1105. pocampus volumes in drug-free depressed patients. World Journal of Biological

Carninci, P., Kasukawa, T., Katayama, S., Gough, J., Frith, M.C., Maeda, N., Oyama, R., Psychiatry 12, 110–118.

Ravasi, T., Lenhard, B., Wells, C., et al., 2005. The transcriptional landscape of the Graff, J., Mansuy, I.M., 2008. Epigenetic codes in cognition and behaviour.

mammalian genome. Science 309, 1559–1563. Behavioural Brain Research 192, 70–87.

Cawley, S., Bekiranov, S., Ng, H.H., Kapranov, P., Sekinger, E.A., Kampa, D., Piccolboni, Graur, D., Zheng, Y., Price, N., Azevedo, R.B., Zufall, R.A., Elhaik, E., 2013. On the

A., Sementchenko, V., Cheng, J., Williams, A.J., et al., 2004. Unbiased mapping of immortality of television sets: “function” in the human genome according to the

transcription factor binding sites along human chromosomes 21 and 22 points evolution-free gospel of ENCODE. Genome Biology and Evolution 5 (3), 578–590.

to widespread regulation of noncoding RNAs. Cell 116, 499–509. Green, P., Ewing, B., 2013. Comment on “Evidence of abundant purifying selection

Chakraborty, D., Kappei, D., Theis, M., Nitzsche, A., Ding, L., Paszkowski, R.M., Suren- in humans for recently acquired regulatory functions”. Science 340, 682.

dranath, V., Berger, N., Schulz, H., Saar, K., et al., 2012. Combined RNAi and Guttman, M., Amit, I., Garber, M., French, C., Lin, M.F., Feldser, D., Huarte, M., Zuk,

localization for functionally dissecting long noncoding RNAs. Nature Methods O., Carey, B.W., Cassady, J.P., et al., 2009. Chromatin signature reveals over a

9, 360–362. thousand highly conserved large non-coding RNAs in mammals. Nature 458,

Chiba, M., Kiyosawa, H., Hiraiwa, N., Ohkohchi, N., Yasue, H., 2009. Existence of 223–227.

Pink1 antisense RNAs in mouse and their localization. Cytogenetic and Genome Guttman, M., Rinn, J.L., 2012. Modular regulatory principles of large non-coding

Research 126, 259–270. RNAs. Nature 482, 339–346.

Chu, C., Qu, K., Zhong, F.L., Artandi, S.E., Chang, H.Y., 2011. Genomic maps of long Hashimoto-Torii, K., Motoyama, J., Hui, C.C., Kuroiwa, A., Nakafuku, M., Shimamura,

noncoding RNA occupancy reveal principles of RNA-chromatin interactions. K., 2003. Differential activities of Sonic hedgehog mediated by Gli transcription

Molecular Cell 44, 667–678. factors define distinct neuronal subtypes in the dorsal thalamus. Mechanisms

Chodroff, R.A., Goodstadt, L., Sirey, T.M., Oliver, P.L., Davies, K.E., Green, E.D., Molnar, of Development 120, 1097–1111.

Z., Ponting, C.P., 2010. Long noncoding RNA genes: conservation of sequence and Huarte, M., Rinn, J.L., 2010. Large non-coding RNAs: missing links in cancer? Human

brain expression among diverse amniotes. Genome Biology 11, R72. Molecular Genetics 19, R152–R161.

Chung, D.W., Rudnicki, D.D., Yu, L., Margolis, R.L., 2011. A natural antisense tran- Hung, T., Wang, Y., Lin, M.F., Koegel, A.K., Kotake, Y., Grant, G.D., Horlings, H.M., Shah,

script at the Huntington’s disease repeat locus regulates HTT expression. Human N., Umbricht, C., Wang, P., et al., 2011. Extensive and coordinated transcription

Molecular Genetics 20, 3467–3477. of noncoding RNAs within cell-cycle promoters. Nature Genetics 43, 621–629.

Clark, M.B., Johnston, R.L., Inostroza-Ponta, M., Fox, A.H., Fortini, E., Moscato, P., Johnson, R., Teh, C.H., Jia, H., Vanisri, R.R., Pandey, T., Lu, Z.H., Buckley, N.J., Stanton,

Dinger, M.E., Mattick, J.S., 2012. Genome-wide analysis of long noncoding RNA L.W., Lipovich, L., 2009. Regulation of neural macroRNAs by the transcriptional

stability. Genome Research 22, 885–898. repressor REST. RNA 15, 85–96.

Cozzolino, M., Ferri, A., Valle, C., Carri, M.T., 2012. Mitochondria and ALS: impli- Johnson, R., Richter, N., Jauch, R., Gaughwin, P.M., Zuccato, C., Cattaneo, E., Stanton,

cations from novel genes and pathways. Molecular and Cellular Neuroscience, L.W., 2010. The human accelerated region 1 noncoding RNA is repressed by REST

http://dx.doi.org/10.1016/j.mcn.2012.06.001. in Huntington’s disease. Physiological Genomics 41, 269–274.

Da, S.L., Baldassarre, A., Masotti, A., 2012. Bioinformatics tools and novel challenges Johnson, R., 2012. Long non-coding RNAs in Huntington’s disease neurodegenera-

in long non-coding RNAs (lncRNAs) functional analysis. International Journal of tion. Neurobiology of Disease 46, 245–254.

Molecular Sciences 13, 97–114. Kang, H., Schuman, E.M., 1995. Long-lasting neurotrophin-induced enhancement of

Dell’Osso, L., Del, D.A., Veltri, A., Bianchi, C., Roncaglia, I., Carlini, M., Massimetti, G., synaptic transmission in the adult hippocampus. Science 267, 1658–1662.

Catena, D.M., Vizzaccaro, C., Marazziti, D., et al., 2010. Associations between Kapranov, P., Cheng, J., Dike, S., Nix, D.A., Duttagupta, R., Willingham, A.T., Stadler,

brain-derived neurotrophic factor plasma levels and severity of the illness, P.F., Hertel, J., Hackermuller, J., Hofacker, I.L., et al., 2007. RNA maps reveal new

recurrence and symptoms in depressed patients. Neuropsychobiology 62, RNA classes and a possible function for pervasive transcription. Science 316,

207–212. 1484–1488.

Derrien, T., Johnson, R., Bussotti, G., Tanzer, A., Djebali, S., Tilgner, H., Guernec, G., Kapranov, P., St, L.G., Raz, T., Ozsolak, F., Reynolds, C.P., Sorensen, P.H., Reaman, G.,

Martin, D., Merkel, A., Knowles, D.G., et al., 2012. The GENCODE v7 catalog of Milos, P., Arceci, R.J., Thompson, J.F., et al., 2010. The majority of total nuclear-

human long noncoding RNAs: analysis of their gene structure, evolution, and encoded non-ribosomal RNA in a human cell is ‘dark matter’ un-annotated RNA.

expression. Genome Research 22, 1775–1789. BMC Biology 8, 149.

Dinger, M.E., Amaral, P.P., Mercer, T.R., Pang, K.C., Bruce, S.J., Gardiner, B.B., Askarian- Kemenes, I., Kemenes, G., Andrew, R.J., Benjamin, P.R., O’Shea, M., 2002. Critical time-

Amiri, M.E., Ru, K., Solda, G., Simons, C., et al., 2008a. Long noncoding RNAs in window for NO-cGMP-dependent long-term memory formation after one-trial

mouse embryonic stem cell pluripotency and differentiation. Genome Research appetitive conditioning. Journal of Neuroscience 22, 1414–1425.

18, 1433–1445. Kennedy, M.B., 1998. Signal transduction molecules at the glutamatergic postsynap-

Dinger, M.E., Pang, K.C., Mercer, T.R., Mattick, J.S., 2008b. Differentiating protein- tic membrane. Brain Research. Brain Research Reviews 26, 243–257.

coding and noncoding RNA: challenges and ambiguities. PLoS Computational Kordower, J.H., Chu, Y., Stebbins, G.T., DeKosky, S.T., Cochran, E.J., Bennett, D., Muf-

Biology 4, e1000176. son, E.J., 2001. Loss and atrophy of layer II entorhinal cortex neurons in elderly

Doi, H., Okamura, K., Bauer, P.O., Furukawa, Y., Shimizu, H., Kurosawa, M., Machida, people with mild cognitive impairment. Annals of Neurology 49, 202–213.

Y., Miyazaki, H., Mitsui, K., Kuroiwa, Y., Nukina, N., 2008. RNA-binding protein Korneev, S.A., Park, J.H., O’Shea, M., 1999. Neuronal expression of neural nitric oxide

TLS is a major nuclear aggregate-interacting protein in huntingtin exon 1 with synthase (nNOS) protein is suppressed by an antisense RNA transcribed from an

expanded polyglutamine-expressing cells. Journal of Biological Chemistry 283, NOS pseudogene. Journal of Neuroscience 19, 7711–7720.

6489–6500. Korneev, S.A., Straub, V., Kemenes, I., Korneeva, E.I., Ott, S.R., Benjamin, P.R., O’Shea,

Ebisuya, M., Yamamoto, T., Nakajima, M., Nishida, E., 2008. Ripples from M., 2005. Timed and targeted differential regulation of nitric oxide synthase

neighbouring transcription. Nature Cell Biology 10, 1106–1113. (NOS) and anti-NOS genes by reward conditioning leading to long-term memory

Eddy, S.R., 2012. The C-value paradox, junk DNA and ENCODE. Current Biology 22, formation. Journal of Neuroscience 25, 1188–1192.

R898–R899. Laske, C., Stellos, K., Hoffmann, N., Stransky, E., Straten, G., Eschweiler, G.W.,

ENCODE Project Consortium, 2012. An integrated encyclopedia of DNA. Elements in Leyhe, T., 2011. Higher BDNF serum levels predict slower cognitive decline in

the human genome. Nature 489, 57–74. Alzheimer’s disease patients. International Journal of Neuropsychopharmaco-

Faghihi, M.A., Modarresi, F., Khalil, A.M., Wood, D.E., Sahagan, B.G., Morgan, T.E., logy 14, 399–404.

Finch, C.E., St, L.G.R., Kenny, P.J., Wahlestedt, C., 2008. Expression of a noncoding Lanz, R.B., McKenna, N.J., Onate, S.A., Albrecht, U., Wong, J., Tsai, S.Y., Tsai, M.J.,

RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation O’Malley, B.W., 1999. A steroid receptor coactivator, SRA, functions as an RNA

of beta-secretase. Nature Medicine 14, 723–730. and is present in an SRC-1 complex. Cell 97, 17–27.

Fantes, J., Ragge, N.K., Lynch, S.A., McGill, N.I., Collin, J.R., Howard-Peebles, P.N., Hay- Lee, R.C., Feinbaum, R.L., Ambros, V., 1993. The C. elegans heterochronic gene lin-4

ward, C., Vivian, A.J., Williamson, K., van Heyningen, V., FitzPatrick, D.R., 2003. encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854.

Mutations in SOX2 cause anophthalmia. Nature Genetics 33, 461–463. Lein, E.S., Hawrylycz, M.J., Ao, N., Ayres, M., Bensinger, A., Bernard, A., Boe, A.F.,

Feng, J., Bi, C., Clark, B.S., Mady, R., Shah, P., Kohtz, J.D., 2006. The Evf-2 noncoding Boguski, M.S., Brockway, K.S., Byrnes, E.J., et al., 2007. Genome-wide atlas of

RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a gene expression in the adult mouse brain. Nature 445, 168–176.

Dlx-2 transcriptional coactivator. Genes and Development 20, 1470–1484. Lepicard, E.M., Mizuno, K., Antunes-Martins, A., von Hertzen, L.S., Giese, K.P.,

Figurov, A., Pozzo-Miller, L.D., Olafsson, P., Wang, T., Lu, B., 1996. Regulation of synap- 2006. An endogenous inhibitor of calcium/calmodulin-dependent kinase II is

tic responses to high-frequency stimulation and LTP by neurotrophins in the up-regulated during consolidation of fear memory. European Journal of Neuro-

hippocampus. Nature 381, 706–709. science 23, 3063–3070.

Fiore, R., Khudayberdiev, S., Saba, R., Schratt, G., 2011. MicroRNA function in the Leygue, E., 2007. Steroid receptor RNA activator (SRA1): unusual bifaceted gene

nervous system. Progress in Molecular Biology and Translational Science 102, products with suspected relevance to breast cancer. Nuclear Receptor Signaling

47–100. 5, e6.

Frade, J.M., Lopez-Sanchez, N., 2010. A novel hypothesis for Alzheimer disease based Lin, D., Pestova, T.V., Hellen, C.U., Tiedge, H., 2008. Translational control by a small

on neuronal tetraploidy induced by p75 (NTR). Cell Cycle 9, 1934–1941. RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase

Furuno, M., Pang, K.C., Ninomiya, N., Fukuda, S., Frith, M.C., Bult, C., Kai, C., Kawai, J., mechanism. Molecular and Cellular Biology 28, 3008–3019.

Carninci, P., Hayashizaki, Y., et al., 2006. Clusters of internally primed transcripts Lin, M., Pedrosa, E., Shah, A., Hrabovsky, A., Maqbool, S., Zheng, D., Lachman, H.M.,

reveal novel long noncoding RNAs. PLoS Genetics 2, e37. 2011. RNA-Seq of human neurons derived from iPS cells reveals candidate long

P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80 79

non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. PLoS Orom, U.A., Derrien, T., Beringer, M., Gumireddy, K., Gardini, A., Bussotti, G., Lai, F.,

ONE 6, e23356. Zytnicki, M., Notredame, C., Huang, Q., et al., 2010. Long noncoding RNAs with

Ling, K.H., Hewitt, C.A., Beissbarth, T., Hyde, L., Cheah, P.S., Smyth, G.K., Tan, S.S., Hahn, enhancer-like function in human cells. Cell 143, 46–58.

C.N., Thomas, T., Thomas, P.Q., Scott, H.S., 2011. Spatiotemporal regulation of Parenti, R., Paratore, S., Torrisi, A., Cavallaro, S., 2007. A natural antisense tran-

multiple overlapping sense and novel natural antisense transcripts at the Nrgn script against Rad18, specifically expressed in neurons and upregulated

and Camk2n1 gene loci during mouse cerebral corticogenesis. Cerebral Cortex during beta-amyloid-induced apoptosis. European Journal of Neuroscience 26,

21, 683–697. 2444–2457.

Lipovich, L., Dachet, F., Cai, J., Bagla, S., Balan, K., Jia, H., Loeb, J.A., 2012. Activity- Plath, K., Mlynarczyk-Evans, S., Nusinow, D.A., Panning, B., 2002. Xist RNA and

dependent human brain coding/noncoding gene regulatory networks. Genetics the mechanism of X chromosome inactivation. Annual Review of Genetics 36,

192, 1133–1148. 233–278.

Lipovich, L., Tarca, A.L., Cai, J., Jia, H., Chugani, H.T., Sterner, K.N., Grossman, L.I., Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, W.J., Pandolfi, P.P., 2010. A

Uddin, M., Hof, P.R., Sherwood, C.C., et al., 2013. Developmental changes in the coding-independent function of gene and pseudogene mRNAs regulates tumour

transcriptome of human cerebral cortex tissue: long noncoding RNA transcripts. biology. Nature 465, 1033–1038.

Cereb Cortex [Epub ahead of print]. Pollard, K.S., Salama, S.R., Lambert, N., Lambot, M.A., Coppens, S., Pedersen, J.S., Katz-

Lisman, J., Schulman, H., Cline, H., 2002. The molecular basis of CaMKII function in man, S., King, B., Onodera, C., Siepel, A., et al., 2006. An RNA gene expressed during

synaptic and behavioural memory. Nature Reviews Neuroscience 3, 175–190. cortical development evolved rapidly in humans. Nature 167, 172.

Liu, X., Liu, L., Xu, Q., Wu, P., Zuo, X., Ji, A., 2012. MicroRNA as a novel drug target for Pokrishevsky, E., Grad, L.I., Yousefi, M., Wang, J., Mackenzie, I.R., Cashman, N.R., 2012.

cancer therapy. Expert Opinion on Biological Therapy 12, 573–580. Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1

Lukiw, W.J., Handley, P., Wong, L., Crapper, M.D., 1992. BC200 RNA in normal in amyotrophic lateral sclerosis. PLoS ONE 7, e35050.

human neocortex, non-Alzheimer dementia (NAD), and senile dementia of the Ponjavic, J., Ponting, C.P., 2007. The long and the short of RNA maps. Bioessays 29,

Alzheimer type (AD). Neurochemical Research 17, 591–597. 1077–1080.

Luo, K.R., Hong, C.J., Liou, Y.J., Hou, S.J., Huang, Y.H., Tsai, S.J., 2010. Differential regula- Ponjavic, J., Ponting, C.P., Lunter, G., 2007. Functionality or transcriptional noise? Evi-

tion of neurotrophin S100B and BDNF in two rat models of depression. Progress dence for selection within long noncoding RNAs. Genome Research 17, 556–565.

in Neuro-Psychopharmacology and Biological Psychiatry 34, 1433–1439. Ponjavic, J., Oliver, P.L., Lunter, G., Ponting, C.P., 2009. Genomic and transcriptional

Mattick, J.S., 2007. A new paradigm for developmental biology. Journal of Experi- co-localization of protein-coding and long non-coding RNA pairs in the devel-

mental Biology 210, 1526–1547. oping brain. PLoS Genetics 5, e1000617.

Martick, M., Horan, L.H., Noller, H.F., Scott, W.G., 2008. A discontinuous hammerhead Ponting, C.P., Oliver, P.L., Reik, W., 2009. Evolution and functions of long noncoding

ribozyme embedded in a mammalian messenger RNA. Nature 454, 899–902. RNAs. Cell 136, 629–641.

Massone, S., Vassallo, I., Fiorino, G., Castelnuovo, M., Barbieri, F., Borghi, R., Tabaton, Pruunsild, P., Kazantseva, A., Aid, T., Palm, K., Timmusk, T., 2007. Dissecting the

M., Robello, M., Gatta, E., Russo, C., et al., 2011. 17A, a novel non-coding RNA, human BDNF locus: bidirectional transcription, complex splicing, and multiple

regulates GABA B alternative splicing and signaling in response to inflammatory promoters. Genomics 90, 397–406.

stimuli and in Alzheimer disease. Neurobiology of Disease 41, 308–317. Rackham, O., Shearwood, A.M., Mercer, T.R., Davies, S.M., Mattick, J.S., Filipovska, A.,

Mercer, T.R., Dinger, M.E., Sunkin, S.M., Mehler, M.F., Mattick, J.S., 2008. Specific 2011. Long noncoding RNAs are generated from the mitochondrial genome and

expression of long noncoding RNAs in the mouse brain. Proceedings of the regulated by nuclear-encoded proteins. RNA 17, 2085–2093.

National Academy of Sciences of the United States of America 105, 716–721. Rapicavoli, N.A., Poth, E.M., Blackshaw, S., 2010. The long noncoding RNA RNCR2

Mercer, T.R., Dinger, M.E., Mattick, J.S., 2009. Long non-coding RNAs: insights into directs mouse retinal cell specification. BMC Developmental Biology 10, 49.

functions. Nature Reviews Genetics 10, 155–159. Rapicavoli, N.A., Poth, E.M., Zhu, H., Blackshaw, S., 2011. The long noncoding RNA

Mercer, T.R., Qureshi, I.A., Gokhan, S., Dinger, M.E., Li, G., Mattick, J.S., Mehler, M.F., Six3OS acts in trans to regulate retinal development by modulating Six3 activity.

2010. Long noncoding RNAs in neuronal-glial fate specification and oligoden- Neural Development 6, 32.

drocyte lineage maturation. BMC Neuroscience 11, 14. Ravasi, T., Suzuki, H., Pang, K.C., Katayama, S., Furuno, M., Okunishi, R., Fukuda, S.,

Meyer, N.P., Roelink, H., 2003. The amino-terminal region of Gli3 antagonizes the Ru, K., Frith, M.C., Gongora, M.M., et al., 2006. Experimental validation of the

Shh response and acts in dorsoventral fate specification in the developing spinal regulated expression of large numbers of non-coding RNAs from the mouse

cord. Developmental Biology 257, 343–355. genome. Genome Research 16, 11–19.

Mercer, T.R., Wilhelm, D., Dinger, M.E., Solda, G., Korbie, D.J., Glazov, E.A., Truong, V., Sai, Y., Zou, Z., Peng, K., Dong, Z., 2012. The Parkinson’s disease-related genes act

Schwenke, M., Simons, C., Matthaei, K.I., et al., 2011. Expression of distinct RNAs in mitochondrial homeostasis. Neuroscience and Biobehavioral Reviews 36,



from 3 untranslated regions. Nucleic Acids Research 39, 2393–2403. 2034–2043.

Minati, L., Edginton, T., Bruzzone, M.G., Giaccone, G., 2009. Current concepts Scheele, C., Petrovic, N., Faghihi, M.A., Lassmann, T., Fredriksson, K., Rooyackers, O.,

in Alzheimer’s disease: a multidisciplinary review. American Journal of Wahlestedt, C., Good, L., Timmons, J.A., 2007. The human PINK1 locus is reg-

Alzheimer’s Disease and Other Dementias 24, 95–121. ulated in vivo by a non-coding natural antisense RNA during modulation of

Modarresi, F., Faghihi, M.A., Lopez-Toledano, M.A., Fatemi, R.P., Magistri, M., mitochondrial function. BMC Genomics 8, 74.

Brothers, S.P., van der Brug, M.P., Wahlestedt, C., 2012. Inhibition of natural anti- Seong, I.S., Woda, J.M., Song, J.J., Lloret, A., Abeyrathne, P.D., Woo, C.J., Gregory, G.,

sense transcripts in vivo results in gene-specific transcriptional upregulation. Lee, J.M., Wheeler, V.C., Walz, T., et al., 2010. Huntingtin facilitates polycomb

Nature Biotechnology 30, 453–459. repressive complex 2. Human Molecular Genetics 19, 573–583.

Morais, V.A., Verstreken, P., Roethig, A., Smet, J., Snellinx, A., Vanbrabant, M., Haddad, Shimojo, M., 2008. Huntingtin regulates RE1-silencing transcription factor/neuron-

D., Frezza, C., Mandemakers, W., Vogt-Weisenhorn, D., et al., 2009. Parkinson’s restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a

disease mutations in PINK1 result in decreased complex I activity and deficient complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin

synaptic function. EMBO Molecular Medicine 1, 99–111. p150 Glued. Journal of Biological Chemistry 283, 34880–34886.

Mucke, L., Masliah, E., Johnson, W.B., Ruppe, M.D., Alford, M., Rockenstein, E.M., Sone, M., Hayashi, T., Tarui, H., Agata, K., Takeichi, M., Nakagawa, S., 2007. The mRNA-

Forss-Petter, S., Pietropaolo, M., Mallory, M., Abraham, C.R., 1994. Synap- like noncoding RNA Gomafu constitutes a novel nuclear domain in a subset of

totrophic effects of human amyloid beta protein precursors in the cortex of neurons. Journal of Cell Science 120, 2498–2506.

transgenic mice. Brain Research 666, 151–167. St, L.G.R., Wahlestedt, C., 2007. Noncoding RNAs: couplers of analog and digital

Muddashetty, R., Khanam, T., Kondrashov, A., Bundman, M., Iacoangeli, A., Kremer- information in nervous system function? Trends in Neurosciences 30, 612–621.

skothen, J., Duning, K., Barnekow, A., Huttenhofer, A., Tiedge, H., et al., 2002. Tani, H., Mizutani, R., Salam, K.A., Tano, K., Ijiri, K., Wakamatsu, A., Isogai, T., Suzuki,

Poly(A)-binding protein is associated with neuronal BC1 and BC200 ribonucleo- Y., Akimitsu, N., 2012. Genome-wide determination of RNA stability reveals

protein particles. Journal of Molecular Biology 321, 433–445. hundreds of short-lived noncoding transcripts in mammals. Genome Research

Muller, U., 1996. Inhibition of nitric oxide synthase impairs a distinct form of long- 22, 947–956.

term memory in the honeybee, Apis mellifera. Neuron 16, 541–549. Tochitani, S., Hayashizaki, Y., 2008. Nkx2.2 antisense RNA overexpression enhanced

Mus, E., Hof, P.R., Tiedge, H., 2007. Dendritic BC200 RNA in aging and in Alzheimer’s oligodendrocytic differentiation. Biochemical and Biophysical Research Com-

disease. Proceedings of the National Academy of Sciences of the United States munications 372, 691–696.

of America 104, 10679–10684. Wang, H., Iacoangeli, A., Popp, S., Muslimov, I.A., Imataka, H., Sonenberg, N., Lomakin,

Nagano, T., Fraser, P., 2011. No-nonsense functions for long noncoding RNAs. Cell I.B., Tiedge, H., 2002. Dendritic BC1 RNA: functional role in regulation of trans-

145, 178–181. lation initiation. Journal of Neuroscience 22, 10232–10241.

Nakaya, H.I., Amaral, P.P., Louro, R., Lopes, A., Fachel, A.A., Moreira, Y.B., El-Jundi, T.A., Wang, J., Zhang, J., Zheng, H., Li, J., Liu, D., Li, H., Samudrala, R., Yu, J., Wong, G.K.,

Da, S.A., Reis, E.M., Verjovski-Almeida, S., 2007. Genome mapping and expression 2004. Mouse transcriptome: neutral evolution of ‘non-coding’ complementary

analyses of human intronic noncoding RNAs reveal tissue-specific patterns and DNAs. Nature 431 (1), 757.

enrichment in genes related to regulation of transcription. Genome Biology 8, Wang, X., Arai, S., Song, X., Reichart, D., Du, K., Pascual, G., Tempst, P., Rosenfeld,

R43. M.G., Glass, C.K., Kurokawa, R., 2008. Induced ncRNAs allosterically modify RNA-

Ng, S.Y., Johnson, R., Stanton, L.W., 2012. Human long non-coding RNAs promote binding proteins in cis to inhibit transcription. Nature 454, 126–130.

pluripotency and neuronal differentiation by association with chromatin mod- Washietl, S., Findeiss, S., Muller, S.A., Kalkhof, S., von Bergen, M., Hofacker, I.L.,

ifiers and transcription factors. EMBO Journal 31, 522–533. Stadler, P.F., Goldman, N., 2011. RNAcode: robust discrimination of coding and

Niu, D.K., Jiang, L., 2013. Can ENCODE tell us how much junk DNA we carry in our noncoding regions in comparative sequence data. RNA 17, 578–594.

genome? Biochemical and Biophysical Research Communications 430, 1343. Washietl, S., Hofacker, I.L., Lukasser, M., Huttenhofer, A., Stadler, P.F., 2005. Map-

Okazaki, Y., Furuno, M., Kasukawa, T., Adachi, J., Bono, H., Kondo, S., Nikaido, I., ping of conserved RNA secondary structures predicts thousands of functional

Osato, N., Saito, R., Suzuki, H., et al., 2002. Analysis of the mouse transcrip- noncoding RNAs in the human genome. Nature Biotechnology 23, 1383–1390.

tome based on functional annotation of 60,770 full-length cDNAs. Nature 420, Werner, A., Sayer, J.A., 2009. Naturally occurring antisense RNA: function and mech-

563–573. anisms of action. Current Opinion in Nephrology and Hypertension 18, 343–349.

80 P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80

Wilusz, J.E., Sunwoo, H., Spector, D.L., 2009. Long noncoding RNAs: functional sur- Zeng, Y., Zhao, D., Xie, C.W., 2010. Neurotrophins enhance CaMKII activity and res-

prises from the RNA world. Genes and Development 23, 1494–1504. cue amyloid-beta-induced deficits in hippocampal synaptic plasticity. Journal

Wright, M.W., Bruford, E.A., 2011. Naming ‘junk’: human non-protein coding RNA of Alzheimer’s Disease 21, 823–831.

(ncRNA) gene nomenclature. Human Genomics 5, 90–98. Zhao, J., Ohsumi, T.K., Kung, J.T., Ogawa, Y., Grau, D.J., Sarma, K., Song, J.J., Kingston,

Wu, P., Zuo, X.L., Ji, A.M., 2012. Stroke-induced microRNAs: the potential therapeutic R.E., Borowsky, M., Lee, J.T., 2010. Genome-wide identification of polycomb-

role for stroke. Experimental and Therapeutics Medicine 3, 571–576 (Review). associated RNAs by RIP-seq. Molecular Cell 40, 939–953.

Yamada, K., Mizuno, M., Nabeshima, T., 2002. Role for brain-derived neurotrophic Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella,

factor in learning and memory. Life Sciences 70, 735–744. T., Leavitt, B.R., Hayden, M.R., Timmusk, T., Rigamonti, D., Cattaneo, E., 2003.

Yang, L., Duff, M.O., Graveley, B.R., Carmichael, G.G., Chen, L.L., 2011. Genomewide Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-

characterization of non-polyadenylated RNAs. Genome Biology 12, R16. controlled neuronal genes. Nature Genetics 35, 76–83.