Sense and antisense RNA are not toxic in Drosophila models of C9orf72-associated ALS/FTD

Moens, Thomas; Mizielinska, Sarah; Niccoli, Teresa; Mitchell, Jamie S.; Thoeng, Annora; Ridler, Charlotte; Grönke, Sebastian; Eßer, Jacqueline; Heslegrave, Amanda; Zetterberg, Henrik; Partridge, Linda; Isaacs, Adrian M.

doi:10.1007/s00401-017-1798-3

Cited by 59 publications

(87 citation statements)

References 59 publications

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“…An expansion of G4C2 repeats within the first intron of the C9ORF72 gene is the main genetic cause of ALS/FTD (DeJesus‐Hernandez et al , ; Renton et al , ). Sense and antisense transcripts containing these repeats are RAN‐translated into toxic DPR proteins (Ash et al , ; Gendron et al , ; Mori et al , ; Zu et al , ), which is a major pathogenic event in cell and animal models of ALS/FTD (Tran et al , ; Jiang et al , ; Liu et al , ; Moens et al , ). However, the molecular mechanisms by which expanded sense G4C2 and antisense C4G2 repeats are translated remain to be fully characterized.…”

Section: Discussionmentioning

confidence: 99%

“…The EMBO Journal 39: e100574 | 2020DiscussionAn expansion of G4C2 repeats within the first intron of the C9ORF72 gene is the main genetic cause of ALS/FTD(DeJesus-Hernandez et al, 2011;Renton et al, 2011). Sense and antisense transcripts containing these repeats are RAN-translated into toxic DPR proteinsGendron et al, 2013;Mori et al, 2013;Zu et al, 2013), which is a major pathogenic event in cell and animal models of ALS/FTDJiang et al, 2016;Liu et al, 2016;Moens et al, 2018)…”

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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: 99%

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

et al. 2020

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“…As introduced above, there is compelling evidence that arginine-rich DPRs produced by C9orf72 HREs contribute to pathophysiology (14,(19)(20)(21)(22)(24)(25)(26)34,49,50). We therefore tested whether these molecules are sufficient to recapitulate the mitochondrial transport deficits observed in C9orf72-patient-derived motor neurons.…”

Section: Arginine-rich Dprs Disrupt Microtubule-based Transport In Hementioning

confidence: 98%

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

Fumagalli

Young

Boeynaems

et al. 2019

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Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we use human induced pluripotent stem cell-derived motor neurons to show that C9orf72 repeat expansions impair microtubule-based transport of mitochondria, a process critical for maintenance of neuronal function. Cargo transport defects are recapitulated by treating healthy neurons with the arginine-rich dipeptide repeat proteins (DPRs) that are produced by the hexanucleotide repeat expansions. Single-molecule imaging shows that these DPRs perturb motility of purified kinesin-1 and cytoplasmic dynein-1 motors along microtubules in vitro. Additional in vitro and in vivo data indicate that the DPRs impair transport by interacting with both microtubules and the motor complexes. We also show that kinesin-1 is enriched in DPR inclusions in patient brains and that increasing the level of this motor strongly suppresses the toxic effects of arginine-rich DPR expression in a Drosophila model. Collectively, our study implicates an inhibitory interaction of arginine-rich DPRs with the axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to novel potential therapeutic strategies. INTRODUCTIONA GGGGCC (G4C2) repeat expansion in the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD) (1,2). Since the association between the hexanucleotide repeat expansions (HREs) and these neurodegenerative diseases was discovered, three non-mutually exclusive pathological mechanisms have been proposed. The first is a loss-of-function scenario due to decreased expression of C9orf72 transcript and protein observed in C9-ALS/FTD patients (1,3). The second is an RNA gain-of-function mechanism caused by the accumulation of expanded repeat transcripts that sequester numerous RNA-binding proteins (4-9). The third proposed mechanism is a protein gain-of-function via the generation of pathological dipeptide repeat proteins (DPRs) originating from non-ATG mediated translation of the expanded repeat transcripts (10-13).This repeat-associated non-ATG (RAN) translation occurs in all reading frames of sense and antisense transcripts resulting in five DPR proteins: poly-GR and poly-GA exclusively from the sense transcript, poly-PR and poly-PA exclusively from the antisense transcript, and poly-GP from both transcripts (10-13). DPRs are found in cytoplasmic inclusions in C9-ALS/FTD post-mortem brain and spinal cord tissue, and also have been detected in motor neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) (5,10,11,(14)(15)(16)(17)(18). The arginine-rich DPRs -poly-PR and poly-GR -are potently toxic in numerous disease models (14,(19)(20)(21)(22)(23)(24)(25)(26)(27), and have been shown to cause mitochondrial (28,29) and endoplasmic reticulum stress (26), as well as disturbances...

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“…RNA binding proteins with which it interfaces. Tran et al addressed this issue in 1 Drosophila by providing evidence that (a) repeats located within introns are less toxic 2 than repeats placed in 5'm 7 G capped and polyadenylated transcripts, and (b) this 3 enhanced toxicity was associated with increased DPR production [21,28]. However, 4 sequence context may also alter the final translated peptides produced by RAN 5 translation and this could influence their toxicity.…”

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The carboxyl-termini of RAN translated GGGGCC nucleotide repeat expansions modulate toxicity in models of ALS/FTD

Flores

Krans

et al. 2020

Preprint

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1An intronic hexanucleotide repeat expansion in C9ORF72 causes familial and sporadic 2 amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This repeat is 3 thought to elicit toxicity through RNA mediated protein sequestration and repeat-4 associated non-AUG (RAN) translation of dipeptide repeat proteins (DPRs). We 5 generated a series of transgenic Drosophila models expressing GGGGCC (G 4 C 2 ) 6 repeats either inside of an artificial intron within a GFP reporter or within the 5' UTR of 7 GFP placed in different downstream reading frames. Expression of 484 intronic repeats 8 elicited minimal alterations in eye morphology, viability, longevity, or larval crawling but 9 did trigger RNA foci formation, consistent with prior reports. In contrast, insertion of 10 repeats into the 5' UTR elicited differential toxicity that was dependent on the reading 11 frame of GFP relative to the repeat. Greater toxicity correlated with a short and 12 unstructured carboxyl terminus in the glycine-arginine (GR) RAN protein reading frame. 13This change in C-terminal sequence triggered nuclear accumulation of all three RAN 14 DPRs. A similar differential toxicity and dependence on the GR carboxyl terminus was 15 observed when repeats were expressed in rodent neurons. The presence of the native 16 carboxyl-termini across all three reading frames was partly protective. Taken together, 17 these findings suggest that carboxyl terminal sequences outside of the repeat region 18 may alter the behavior and toxicity of dipeptide repeat proteins derived from GGGGCC 19 repeats.

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Sense and antisense RNA are not toxic in Drosophila models of C9orf72-associated ALS/FTD

Cited by 59 publications

References 59 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

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

The carboxyl-termini of RAN translated GGGGCC nucleotide repeat expansions modulate toxicity in models of ALS/FTD

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