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Repeat-Associated Non-ATG Translation in Neurological Diseases

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Repeat-Associated Non-ATG Translation in Neurological Diseases Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Repeat-Associated Non-ATG Translation in Neurological Diseases Tao Zu,1,2 Amrutha Pattamatta,1,2 and Laura P.W. Ranum1,2,3,4 1Center for Neuro-Genetics, University of Florida, Gainesville, Florida 32610 2Departments of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610 3Departments of Neurology, College of Medicine, University of Florida, Gainesville, Florida 32610 4Genetics Institute, University of Florida, Gainesville, Florida 32610 Correspondence: [email protected] More than 40 different neurological diseases are caused by microsatellite repeat expansions that locate within translated or untranslated gene regions, including 50 and 30 untranslated regions (UTRs), introns, and protein-coding regions. Expansion mutations are transcribed bidirectionally and have been shown to give rise to proteins, which are synthesized from three reading frames in the absence of an AUG initiation codon through a novel process called repeat-associated non-ATG (RAN) translation. RAN proteins, which were first de- scribed in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1), have now been reported in a growing list of microsatellite expansion diseases. This article reviews what is currently known about RAN proteins in microsatellite expansion diseases and experiments that provide clues on how RAN translation is regulated. icrosatellite repeats, or short repetitive built on inferring the mechanisms of these dis- Mstretches of DNA containing 2–10 nucleo- eases based on the position of the mutations tides are common in the human genome. A sub- within their corresponding genes. For example, set of these sequences has been shown to be un- for diseases such as HD, in which the mutation is stable, and when expanded too many times, can translated as a glutamine stretch that is part of a cause disease. Microsatellite expansions are long open reading frame (ORF), most research known to cause >40 different neurodegenerative has been focused on how the mutant protein, diseases, including Huntington disease (HD), which contains a long polyGln repeat tract, dis- fragile X tremor ataxia syndrome (FXTAS), turbs various cellular functions that result in cel- C9ORF72 amyotrophic lateral sclerosis (ALS)/ lular toxicity and disease. In contrast, the dele- frontotemporal dementia (FTD), and spinocer- terious effects of mutant expansion RNAs or ebellar ataxia types 1, 2, 3, 6, 7, 8, 10, 12, and 17 RNA gain-of-function effects have been the (Ranum and Cooper 2006; Orrand Zoghbi 2007; primary mechanistic focus for diseases charac- Lopez Castel et al. 2010). terized by expansion RNAs located outside ca- A framework for understanding the patho- nonical ORFs. Mutant RNAs produced from genic mechanisms of these diseases has been these noncoding expansion mutations have Editors: Michael B. Mathews, Nahum Sonenberg, and John W.B. Hershey Additional Perspectives on Translation Mechanisms and Control available at www.cshperspectives.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a033019 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press T. Zu et al. been shown to accumulate as nuclear RNA foci translation, which was initially discovered in that sequester RNA-binding proteins (RBPs) spinocerebellar ataxia type 8 (SCA8) and and lead to a loss of their normal function (Ra- DM1, has now been reported in seven different num and Cooper 2006; Scotti and Swanson repeat expansion diseases, including C9orf72 2016). The myotonic dystrophies are the classic ALS/FTD, FXTAS, HD, SCA31, and DM2 (Zu example of this type of disorder. For example, et al. 2011, 2013, 2017; Ash et al. 2013; Mori et al. the myotonic dystrophy type 1 (DM1) and type 2013b; Todd et al. 2013; Banez-Coronel et al. 2 (DM2) mutations, which express CUG or 2015; Ishiguro et al. 2017). In addition to RAN CCUG expansion RNAs, respectively, sequester translation, the bidirectional transcription of the muscleblind-like (MBNL) family of RNA- microsatellite expansion mutations (Cho et al. binding proteins within the nucleus as RNA 2005; Moseley et al. 2006; Ladd et al. 2007; Rud- foci. This sequestration prevents MBNL proteins nicki et al. 2007; Batra et al. 2010; Ranum et al. from binding to their normal RNA-processing 2010) adds further mechanistic complexity to targets, and the resulting MBNL loss-of-func- these disorders, and raises the possibility that tion leads to RNA-processing abnormalities in- one or both expansion transcripts and up to cluding dysregulation of alternative splicing and six RAN proteins contribute to many of these changes in polyadenylation (Ranum and Cooper diseases (Fig. 1). For the translation field, the 2006; Scotti and Swanson 2016). discovery that expansion mutations express The discovery of repeat-associated non- proteins without a canonical AUG-initiation ATG (RAN) translation challenged these mod- codon in multiple reading frames raises mecha- els because it showed that repeat expansion nistic questions about how RAN proteins are mutations can express unexpected repetitive initiated and whether these mutant proteins proteins in all three reading frames without an can be therapeutically targeted (Cleary and AUG initiation codon (Zu et al. 2011). RAN Ranum 2017). poly-(GP) poly-(GA) poly-(WNGME) SCA1 poly-(LPAC) poly-(GR) SCA2 poly-Ser poly-Ala SCA3 poly-Ala poly-Gly SCA6 (M) poly-Gln SCA7 DM2 DM1 SCA17 HDL2 C9ORF72 ALS/FTD DRPLA SCA10 HD SCA31 SMBA SCA12 FXTAS SCA8 Sense CAG CAG CTG CAG CGG GGGGCC TGGAA ATTCT CCTG CTG CTG CTG 5′UTR Exon Intron Exon Intron Exon 3′UTR CTG CCG GGCCCC CTG CTG TTCCA AGAAT CAGG CAG CAG CAG FXTAS SCA7 HDL2 SCA8 HD C9ORF72 ALS/FTD DM2 (M) poly-Gln poly-Pro poly-(PA) poly-Leu poly-Ala Antisense poly-Ala poly-(PR) poly-Cys poly-(QAGR) poly-Gln poly-(GP) poly-Ala Figure 1. Bidirectional transcription and repeat-associated non-ATG (RAN) translation in repeat expansion disorders. Antisense transcripts and RAN proteins have been observed in a growing number of microsatellite expansions, including spinocerebellar ataxia type 8 (SCA8), myotonic dystrophy type 1 (DM1), myotonic dys- trophy type 2 (DM2), fragile X tremor ataxia syndrome (FXTAS), C9ORF72 amyotrophic lateral sclerosis (ALS)/ frontotemporal dementia (FTD), Huntington disease (HD), and spinocerebellar ataxia type 31 (SCA31). RAN proteins that have been identified in various expansion diseases and confirmed in patient tissues are shown in red. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a033019 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press RAN Translation in Neurological Diseases RAN TRANSLATION Additional cell-culture experiments showed that hairpin-forming CAG and CUG expan- The Discovery of RAN Translation in SCA8 sions express RAN proteins without an AUG and DM1 initiation codon (Zu et al. 2011). Steady-state SCA8 is an autosomal dominant, neurodegener- levels of RAN proteins were differentially affect- ative disease caused by a CTG•CAG repeat ex- ed by repeat length in transfected cells with no pansion. In2006,itwasrecognized thattheSCA8 RAN protein accumulation detectable with 20 expansion mutation is bidirectionally tran- CAG repeats or less, polyGln accumulation ev- scribed and produces both CUG (ATXN8OS) ident at ≥42 repeats, polySer at ≥58, and polyAla and CAG (ATXN8) expansion RNAs, which are at ≥73 repeats (Zu et al. 2011). Because repeat expressed in opposite directions across the ex- length is often correlated with anticipation or pansion mutation (Moseley et al. 2006). The worsening of disease, it is possible that the accu- CUG expansion transcripts form RNA foci, mulation of RAN proteins in multiple reading which have been shown tosequester muscleblind frames with longer repeats exacerbates disease. proteins and are thought to cause RNA gain-of- Finally, Zu et al. developed antibodies to detect function problems (Daughters et al. 2009). In the carboxy-terminal regions of these proteins addition, the expanded CAG ATXN8 transcript in vivo and showed that RAN proteins are ex- expressed in the opposite direction produces a pressed in vivo in both mouse and human dis- nearly pure polyGln protein from an unusual ease tissue (Zu et al. 2011). In SCA8, a novel short ORF that contains an AUG-initiation co- polyAla RAN protein was shown to accumulate don directly upstream of the CAG repeat (Mose- in Purkinje cells and in DM1 a novel polyGln ley et al. 2006). RAN protein expressed from the antisense CAG To understand the relative contributions of expansion transcript was detected in heart, skel- the effects of the ATXN8 encoded polyGln pro- etal muscle, and blood. tein (Moseley et al. 2006), Ranum and col- In summary, CAG and CUG microsatellite leagues attempted to block its expression by mu- expansion RNAs undergo a novel form of trans- tating the upstream ATG initiation codon. lation that leads to the production of homo- Unexpectedly, this mutation did not block ex- polymeric expansion proteins from all three pression of the polyGln protein in transfected reading frames without an AUG-initiation co- cells (Zu et al. 2011). This finding raised the don. The RAN proteins predicted by cell-culture question of whether proteins could be made in experiments accumulate in vivo in both SCA8 other reading frames. To answer this question, and DM1 disease tissue. CAG expansion expression vectors with two stop codons in each reading frame upstream of RAN Proteins in C9ORF72 ALS/FTD the CAG tract were generated to ensure AUG initiation could not occur in any of the reading In 2011, a GGGGCC (G4C2) hexanucleotide re- frames. Additionally, epitope tags in each of the peat expansion located in intron 1 of the chro- three reading frames downstream from the re- mosome 9 open reading frame 72 (C9ORF72) peat were used to tag proteins expressed from gene was reported by two research groups as any of the three frames.
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