Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions

Cooper‐Knock, Johnathan; Walsh, Marianne E.; Higginbottom, Adrian; Highley, J. Robin; Dickman, Mark J.; Edbauer, Dieter; Ince, Paul G.; Wharton, Stephen B.; Wilson, Stuart A.; Kirby, Janine; Hautbergue, Guillaume M.; Shaw, Pamela J.

doi:10.1093/brain/awu120

Cited by 269 publications

(366 citation statements)

References 44 publications

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“…Second, both sense and antisense repeat RNA were found to be mainly localized to the cytoplasm, both diffusely as well as in RNA foci. While in C9orf72 patients most RNA foci have been found to be located in the nucleus, cytoplasmic RNA foci have also been found in postmortem tissue [11,12,34], as well as in patient-derived cell cultures [17]. These data suggest that RNA toxicity might be mediated by cytoplasmic repeat RNA, which might explain why no correlation between extent of nuclear RNA foci and neurodegeneration has been found in postmortem tissue [15].…”

Section: Discussionmentioning

confidence: 92%

“…Therefore, we investigated whether different RNA-binding proteins known to bind GGG GCC repeats, such as Pur-alpha [12,41,51], hnRNPH1 [30] and hnRNPA1 [41], are also able to bind the toxic RNA repeats used in our model. Pur-alpha indeed bound to the toxic sense (~ 70S, 108RO) repeat RNA and, albeit with less affinity, to the toxic antisense (~ 70AS, 108RO AS) repeat RNA (Online Resource 3a).…”

Section: Rna-binding Protein Pur-alpha Prevents the Axonopathy Inducementioning

confidence: 99%

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A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGG GCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

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Section: Discussionmentioning

confidence: 92%

Section: Rna-binding Protein Pur-alpha Prevents the Axonopathy Inducementioning

confidence: 99%

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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“…1). Many of the proteins bound by G 4 C 2 repeats are required for normal RNA processing, including nucleolin, ADAR, hnRNP A1, hnRNP H, SC35, and serine/ arginine-rich splicing factor 1 and serine/arginine-rich splicing factor 2 [66,68,119,121,122], suggesting that neuronal toxicity in ALS might arise from a functional depletion of these essential factors. If so, then blocking the repeat domain might prevent downstream toxicity.…”

Section: Sequestrationmentioning

confidence: 99%

“…These dipeptides are toxic to cells in vitro and in vivo [69,[136][137][138], causing cell death in some cases by disrupting RNA processing within nucleoli [69], or by altering the function of essential proteins such as Unc119 [137], a trafficking factor required for axon development [139]. Moreover, the sequestration of RNA binding proteins by expanded G 4 C 2 RNA may be synergistic with the toxicity induced by RAN translation products [138]: many of the proteins bound by G 4 C 2 RNA catalyze the nuclear export of RNA, potentially facilitating cytoplasmic RAN translation of expanded C9orf72 repeats and accentuating toxicity [121].…”

Section: Alternative Rna-based Mechanismsmentioning

confidence: 99%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

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The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

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“…The C9orf72 RNA repeat expansion may exert its toxic properties via the sequestration of multiple RRM-containing proteins and their subsequent depletion. 117,133,134 Proteins involved in splicing, mRNA nuclear export, and/or translation were significantly enriched as binding partners of the G 4 C 2 repeat expansion. hnRNPA3, hnRNPA2/B1, SFPQ, ILF3, NONO, hnRNP L, IL2BP1, ILF-2, FUS, 133 strong and selective binding to the G 4 C 2 repeat.…”

Section: C9orf72 Mutations In Als: Secrets Unlocked?mentioning

confidence: 99%

The genetic basis of amyotrophic lateral sclerosis: recent breakthroughs

Eykens¹,

Robberecht²

2015

AGG

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Deciphering the genetic architecture of amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disorder of the motor neuron system, is important to understand the etiology of this fatal disease as well as to develop customized ALS therapies based on the patient's genetic fingerprint. In this review, we discuss the genetic basis of ALS, and attempt to link the causal genes to three highly interrelated pathogenic mechanisms: dysproteostasis, RNA dysregulation, and axon dysfunction. In addition, we address the clinical and biological implications of these genetic findings. Furthermore, we explore to what extent genetic knowledge can be converted into targeted and personalized treatments.

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Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions

Cited by 269 publications

References 44 publications

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

The genetic basis of amyotrophic lateral sclerosis: recent breakthroughs

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