CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts

Tabet, Ricardos; Schaeffer, Laure; Freyermuth, Fernande; Jambeau, Mélanie; Workman, Michael J.; Lee, Chao Zong; Lin, Chun Chia; Jiang, Jie; Jansen-West, Karen; Abou‐Hamdan, Hussein; Désaubry, Laurent; Gendron, Tania F.; Petrucelli, Leonard; Martin, Franck; Lagier‐Tourenne, Clotilde

doi:10.1038/s41467-017-02643-5

Cited by 129 publications

(167 citation statements)

References 70 publications

(99 reference statements)

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“…Immunoprecipitation of the polyGA DPR protein followed by LysC digestion and LC‐MS/MS analysis revealed a translation initiation to a CUG near‐cognate codon embedded in a correct Kozak consensus sequence and located 24 nucleotides upstream of the G4C2 repeats (Fig B). This CUG start site of polyGA is identical to the one found in three other independent studies (Green et al , ; Sonobe et al , ; Tabet et al , ). Mass spectrometry indicates that the initial amino acid of the polyGA DPR protein is a methionine, suggesting that the CUG codon is decoded by an initiator Met‐tRNA despite imperfect match.…”

Section: Resultssupporting

confidence: 86%

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: Resultssupporting

confidence: 86%

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

et al. 2020

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“…C9orf72 is believed to cause disease by three putative mechanism(s); haploinsufficiency, sequestration of RNA binding proteins by RNA foci and/or di‐peptide repeat (DPR) mediated toxicity (Mizielinska & Isaacs, ; Shi et al, ; Tabet et al, ). As intranuclear RNA foci are observed in astrocytes in post‐mortem derived material from C9orf72 patients (Lagier‐Tourenne et al, ), we first used fluorescent in situ hybridization (FISH) to confirm the presence of abundant intranuclear RNA foci in mutant astrocytes that were absent in controls (Figure a).…”

Section: Resultsmentioning

confidence: 99%

Mutant C9orf72 human iPSC‐derived astrocytes cause non‐cell autonomous motor neuron pathophysiology

Zhao

Devlin

Chouhan

et al. 2019

Glia

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Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non‐cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72‐mediated ALS. Here, we use a human iPSC‐based model to study the cell autonomous and non‐autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72‐related ALS pathology and, upon co‐culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage‐activated Na+ and K+ currents. Importantly, CRISPR/Cas‐9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell‐autonomous astrocyte pathology and non‐cell autonomous motor neuron pathophysiology.

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“…ª 2019 The Authors EMBO Molecular Medicine 11: e9423 | 2019 UTR that can form nucleic acid secondary structures (Fratta et al, 2012;Reddy et al, 2013;Haeusler et al, 2014); and (ii) an upstream AUG-initiated ORFs (Tabet et al, 2018), which serves as regulatory elements that alter downstream translation of the AUG-initiated ORFs in response to neuronal stress or hyperactivity (Chesnokova et al, 2017). Therefore, given the C9orf72 gene transcripts are most abundant in the brain of human post-mortem tissue (Carithers et al, 2015), it may not be surprising that C9orf72 NRE DPRs are more readily detected within these regions that are directly linked to neurodegenerative disease (Saberi et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

et al. 2019

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Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat‐associated non‐AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated‐PERK and the phosphorylated‐eif2α complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR‐dependent disease pathogenesis in NRE‐linked diseases.

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CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts

Cited by 129 publications

References 70 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

Mutant C9orf72 human iPSC‐derived astrocytes cause non‐cell autonomous motor neuron pathophysiology

Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

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