Deng et al. Molecular Neurodegeneration (2017) 12:90 DOI 10.1186/s13024-017-0232-6 REVIEW Open Access Is amyotrophic lateral sclerosis/ frontotemporal dementia an autophagy disease? Zhiqiang Deng1,2,3, Patricia Sheehan3, Shi Chen1,2* and Zhenyu Yue3* Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that share genetic risk factors and pathological hallmarks. Intriguingly, these shared factors result in a high rate of comorbidity of these diseases in patients. Intracellular protein aggregates are a common pathological hallmark of both diseases. Emerging evidence suggests that impaired RNA processing and disrupted protein homeostasis are two major pathogenic pathways for these diseases. Indeed, recent evidence from genetic and cellular studies of the etiology and pathogenesis of ALS-FTD has suggested that defects in autophagy may underlie various aspects of these diseases. In this review, we discuss the link between genetic mutations, autophagy dysfunction, and the pathogenesis of ALS-FTD. Although dysfunction in a variety of cellular pathways can lead to these diseases, we provide evidence that ALS-FTD is, in many cases, an autophagy disease. Keywords: Amyotrophic lateral sclerosis, Frontotemporal dementia, Autophagy, Disease-associated genes, Autophagy- related genes Background FTD is a form of dementia characterized by focal atro- Though various cellular defects are noted in Amyo- phy of the frontal and anterior temporal lobes of the trophic Lateral Sclerosis (ALS) and Frontotemporal de- brain, called frontaltemporal lobar degeneration (FTLD) mentia (FTD) including dysregulation of RNA [4]. The comorbidity of these diseases in patients and processing, protein aggregation, and oxidative stress, the the shared genetic risk factors suggest ALS and FTD detailed disease mechanisms remain poorly understood represent a continuum of neurodegenerative disorders [1, 2]. Emerging evidence from genetic cases points to a [5]. A common pathological hallmark of both ALS and role of autophagy in ALS-FTD. Here, we review how FTD is the presence of cytoplasmic protein aggregates specific disease-linked mutations affect proper autopha- and inclusions in affected neurons and glia cells [6–8], gic function and protein degradation leading to the suggesting that an impairment in protein degradation speculation that ALS-FTD is, at least in part, an autoph- may contribute to the disease process. In eukaryotic agy disease. cells, the clearance of toxic-aggregated proteins is critical for cell survival, which relies mainly on two protein deg- ALS and FTD radation systems: the ubiquitin-proteasome system ALS is an adult-onset devastating neurodegenerative dis- (UPS) and autophagy [9, 10]. The UPS is mainly used order characterized by progressive degeneration and de- for the degradation of short-lived proteins, while autoph- terioration of upper and lower motor neurons of the agy is preferentially used for the selective degradation of primary motor cortex, spinal cord and brain stem [3]. long-lived proteins and damaged organelles [11]. While the dysfunction of either the UPS or autophagy has been * Correspondence: [email protected]; [email protected] implicated in the formation of ALS-FTD-linked protein 1Brain center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, China aggregates, accumulating evidence suggests that proper 3Department of Neurology, The Friedman Brain Institute, Icahn School of functioning of autophagy is the major determinant of Medicine at Mount Sinai, New York 10029, USA motor neuron survival in ALS [12–15]. Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Deng et al. Molecular Neurodegeneration (2017) 12:90 Page 2 of 11 Autophagic processing Syntaxin17, SNAP29, VAMP7/8) as key mediators of Autophagy is a highly conserved catabolic cellular path- autophagosome-lysosome fusion [21]. way used to degrade proteins and organelles at a basal Autophagy was initially characterized as a non-selective level as well as pathogens and protein aggregates under degradation process. However, accumulating evidence pathological conditions. The endpoint of all autophagic shows that cargo such as damaged mitochondria and ag- pathways is the lysosome though, the three major au- gregated proteins can be selectively degraded by autoph- tophagic pathways (i.e., microautophagy, chaperone- agy to maintain intracellular homeostasis [22–24]. This mediated autophagy, and macroautophagy) utilize differ- process of selective autophagy is carried out by autophagy ent signaling molecules and protein machinery to receptors, which recognize specific cargo (including prompt lysosomal degradation. This review will focus on disease-related proteins) through protein modifications of the role of macroautophagy (hereafter referred to as au- receptors in response to proteotoxic stress [25]. tophagy) in ALS-FTD. Although growing evidence points to an association of Canonical autophagy is under the control of mechanis- autophagic function and the development of ALS and tic target of rapamycin complex 1 (mTORC1), a master FTD [8, 26], the precise role of autophagy in the patho- regulator of diverse signaling pathways, which is regu- genesis of these diseases remains elusive. Here, we re- lated by cellular nutrient levels. Under nutrient-rich con- view recent evidence for the role of ALS-FTD-associated ditions, mTORC1 is active, suppressing the induction of genes in autophagic processing. autophagy by phosphorylating Unc51-like kinase 1 (ULK1) and Transcription Factor EB (TFEB). Starvation ALS-FTD-associated genes and autophagy conditions inhibit the activity of mTORC1 and allow the C9ORF72 induction of autophagy through the dephosphorylation The GGGGCC (G4C2) hexanucleotide repeat expansion of ULK1 and TFEB. Upon dephosphorylation, TFEB in C9ORF72 is the most common genetic cause of ALS- translocates to the nucleus where it functions to upregu- FTD [27]. Multiple pathogenic mechanisms are thought late autophagy and lysosome-associated genes thus pro- to underlie the pathology associated with the G4C2 ex- moting autophagic degradation [16]. Once ULK1 is pansion. This alteration of C9ORF72 may lead to epi- dephosphorylated, it forms a complex that can then genetic changes [28] that result in decreased mRNA phosphorylate Beclin1 [17] and Atg14L [18], two protein levels and the loss-of-function of C9ORF72 [27]. Alter- subunits in the class III phosphoinositol-3-phosphate natively, G4C2 expansion containing transcripts may be kinase VPS34 complex. ULK1-mediated Atg14L phos- subject to repeat-associated non-ATG (RAN) translation phorylation activates VPS34 kinase activity, which is re- that could result in a toxic gain-of-function of dipeptide- quired for the nucleation of the phagophore membrane. repeat proteins [29–31]. Multiple groups have initiated The phagophore then expands to form the isolation studies to develop therapeutic interventions aimed at re- membrane and engulf cytoplasmic contents. This elong- ducing the toxicity of dipeptide-repeat proteins using ation of the isolation membrane is dependent on two gene depletion, peptide, or small molecule strategies to ubiquitin-like conjugation systems. The first involves the decrease RAN translation [32]. Pathologically, post- covalent conjugation of Atg12 to Atg5, a process carried mortem analysis of patients carrying the G4C2 expansion out by Atg7 and Atg10. Atg5-Atg12 complex then binds in C9ORF72 reveals the presence of RNA foci and ubi- Atg16. The second requires Atg7 and Atg3, assisted by quitin/p62 positive inclusions [33–35]. Given these find- Atg5-Atg12-Atg16, leading to the conjugation of phos- ings, much interest has arisen in understanding the phoethanolamine to LC3 [19]. This lipidation of LC3 al- potential link between C9ORF72 and autophagic regula- lows it to associate with the autophagosome membrane tion. Accumulating evidence demonstrates the relevance and aid in cargo sequestration by associating with vari- of C9ORF72 to autophagy, though its precise role in ous autophagy receptors. Eventually, the membrane regulating autophagy is still unknown. Evidence suggests closes and forms a double membrane structure referred C9ORF72 acts in a multi-protein complex with SMCR8 to as an autophagosome [19]. Following cargo sequestra- and WDR41 to regulate the expression and activity of tion, autophagosomes are trafficked along microtubule ULK1 [36]. Further, knockdown of C9ORF72 in MEF tracks. During this transport, autophagosomes can then cells and mice impairs ULK1-mediated autophagy fuse with compartments of the endocytic pathway to nduction, suggesting that C9ORF72 promotes autophagy form an intermediate structure called an amphisome, [36, 37]. Acting in the same complex, C9ORF72 func- which will then fuse with lysosomes for cargo degrad- tions as a guanine nucleotide exchange factor (GEF) to ation [20]. Additional studies