Rethinking Unconventional Translation in Neurodegeneration

Gao, Fen‐Biao; Richter, Joel D.; Cleveland, Don W.

doi:10.1016/j.cell.2017.10.042

Cited by 58 publications

(45 citation statements)

References 58 publications

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“…Ribosome profiling demonstrated that initiation to near‐cognate codons is more common than previously thought and may occur in up to ~30% of mammalian genes (Ingolia et al , ; Fritsch et al , ). These data suggest that translation initiation at near‐cognate codons located upstream of the repeats could be a common pathogenic mechanism in microsatellite expansion diseases, a hypothesis that may warrant further investigations (Gao et al , ). However, translation initiation at near‐cognate codons should occur independently of the presence of downstream repeats, but DPR proteins are observed only in carriers of G4C2 repeat expansions and not in control individuals.…”

Section: Discussionmentioning

confidence: 82%

Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders

et al. 2020

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Expansion of G4C2 repeats within the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Such repeats lead to decreased expression of the autophagy regulator C9ORF72 protein. Furthermore, sense and antisense repeats are translated into toxic dipeptide repeat (DPR) proteins. It is unclear how these repeats are translated, and in which way their translation and the reduced expression of C9ORF72 modulate repeat toxicity. Here, we found that sense and antisense repeats are translated upon initiation at canonical AUG or near‐cognate start codons, resulting in polyGA‐, polyPG‐, and to a lesser degree polyGR‐DPR proteins. However, accumulation of these proteins is prevented by autophagy. Importantly, reduced C9ORF72 levels lead to suboptimal autophagy, thereby impairing clearance of DPR proteins and causing their toxic accumulation, ultimately resulting in neuronal cell death. Of clinical importance, pharmacological compounds activating autophagy can prevent neuronal cell death caused by DPR proteins accumulation. These results suggest the existence of a double‐hit pathogenic mechanism in ALS/FTD, whereby reduced expression of C9ORF72 synergizes with DPR protein accumulation and toxicity.

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Section: Discussionmentioning

confidence: 82%

Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders

et al. 2020

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“…Since the initial discovery of RAN translation, additional microsatellite expansion disorders including Fragile X Tremors Ataxia Syndrome (FXTAS) and Huntingtin’s disease have been added to the list of conditions in which bidirectional expanded transcripts produce RAN proteins [4, 5]. These novel and unexpected peptides contribute to toxicity challenging existing paradigms about disease mechanisms wherever they are found.…”

Section: Ran Translation Beyond Als/ftdmentioning

confidence: 99%

“…A version of IRES translation is Repeat Associated Non-AUG (RAN) translation (Fig. 11.1bii), which has been associated with mutant microsatellite expansions in traditionally noncoding portions of the genome such as untranslated regions (UTRs) or introns, and more recently with coding regions (recently reviewed in [4, 5]). In the absence of an AUG codon, translation is possible because the hairpin structure formed by microsatellite mRNA can mimic the methionine tRNA that initiates translation [6].…”

Section: Introductionmentioning

confidence: 99%

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

Lehmkuhl

Zarnescu

2018

Advances in Neurobiology

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Cells utilize a complex network of proteins to regulate translation, involving post-transcriptional processing of RNA and assembly of the ribosomal unit. Although the complexity provides robust regulation of proteostasis, it also offers several opportunities for translational dysregulation, as has been observed in many neurodegenerative disorders. Defective mRNA localization, mRNA sequatration, inhibited ribogenesis, mutant tRNA synthetases, and translation of hexanucleotide expansions have all been associated with neurodegenerative disease. Here, we review dysregulation of translation in the context of age-related neurodegeneration and discuss novel methods to interrogate translation. This review primarily focuses on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a spectrum disorder heavily associated with RNA metabolism, while also analyzing translational inhibition in the context of related neurodegenerative disorders such as Alzheimer's disease and Huntington's disease and the translation-related pathomechanisms common in neurodegenerative disease.

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“…At other repeats and cellular contexts, RAN translation may utilize cap-independent initiation mechanisms and/ or initiator tRNAs other than tRNAi Met [10,39,40]. Which mechanisms occur in the context of each human disease is unclear and could vary based on gene context, repeat content, and cell type [19,41,42].…”

Section: Introductionmentioning

confidence: 99%

DDX 3X and specific initiation factors modulate FMR 1 repeat‐associated non‐AUG‐initiated translation

Linsalata

Malik

et al. 2019

EMBO Reports

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A CGG trinucleotide repeat expansion in the 5′ UTR of FMR1 causes the neurodegenerative disorder Fragile X‐associated tremor/ataxia syndrome (FXTAS). This repeat supports a non‐canonical mode of protein synthesis known as repeat‐associated, non‐AUG (RAN) translation. The mechanism underlying RAN translation at CGG repeats remains unclear. To identify modifiers of RAN translation and potential therapeutic targets, we performed a candidate‐based screen of eukaryotic initiation factors and RNA helicases in cell‐based assays and a Drosophila melanogaster model of FXTAS. We identified multiple modifiers of toxicity and RAN translation from an expanded CGG repeat in the context of the FMR1 5′UTR. These include the DEAD‐box RNA helicase belle/DDX3X, the helicase accessory factors EIF4B/4H, and the start codon selectivity factors EIF1 and EIF5. Disrupting belle/DDX3X selectively inhibited FMR1 RAN translation in Drosophila in vivo and cultured human cells, and mitigated repeat‐induced toxicity in Drosophila and primary rodent neurons. These findings implicate RNA secondary structure and start codon fidelity as critical elements mediating FMR1 RAN translation and identify potential targets for treating repeat‐associated neurodegeneration.

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Rethinking Unconventional Translation in Neurodegeneration

Cited by 58 publications

References 58 publications

Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders

Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

DDX 3X and specific initiation factors modulate FMR 1 repeat‐associated non‐AUG‐initiated translation

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