Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia

Fratta, Pietro; Poulter, Mark; Lashley, Tammaryn; Rohrer, Jonathan D.; Polke, James M.; Beck, Jon; Ryan, Natalie S.; Moss, Davina J. Hensman; Mizielinska, Sarah; Waite, Adrian James; Lai, Mang Ching; Gendron, Tania F.; Petrucelli, Leonard; Fisher, Elizabeth; Révész, Tamás; Warren, Jason D.; Collinge, John; Isaacs, Adrian M.; Mead, Simon

doi:10.1007/s00401-013-1147-0

Cited by 125 publications

(103 citation statements)

References 32 publications

(39 reference statements)

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“…Interestingly, the C9orf72 protein has been shown to be a key player in regulation of autophagy [49]. Moreover, homozygosity for the repeat expansion does not generate a phenotype in humans that is worse than heterozygosity [18]. Altogether, the current data make loss-of-function rather unlikely to be a causal mechanism, although it remains to be investigated how lossof-function mechanisms might contribute to the disease.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 90%

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: Electronic Supplementary Materialsmentioning

confidence: 90%

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

et al. 2018

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“…24 Haploinsufficiency was initially suggested as a disease mechanism owing to the decreased abundance of V2 and V3 transcripts in c9-ALS cases, and consistent with this hypothesis, reduced expression of selected or total C9orf72 transcripts in C9orf72 repeat expansion carrier-derived cells or tissues have been widely reported. 1,[24][25][26][27][28][29][30][31] Although there is little known about the effects of C9orf72 haploinsufficiency, the development of motor phenotypes in zebrafish and Caenorhabditis elegans owing to downregulation of C9orf72 orthologues supports its role as a disease pathomechanism. 30,32 It has been predicted that C9orf72 proteins may belong to the DENN-like protein family and play roles in Rabmediated cellular trafficking; however, the precise functions and properties of C9orf72 protein are largely unknown owing to a lack of specific antibodies.…”

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confidence: 99%

Isoform‐specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis

Xiao

MacNair

McGoldrick

et al. 2015

Annals of Neurology

121

193

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Objective: A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It has been reported that the repeat expansion causes a downregulation of C9orf72 transcripts, suggesting that haploinsufficiency may contribute to disease pathogenesis. Two protein isoforms are generated from three alternatively spliced transcripts of C9orf72; a long form (C9-L) and a short form (C9-S), and their function(s) are largely unknown owing to lack of specific antibodies. Methods: To investigate C9orf72 protein properties, we developed novel antibodies that recognize either C9-L or C9-S. Multiple techniques, including Western blot, immunohistochemistry, and coimmunoprecipitation, were used to determine the expression levels and subcellular localizations of C9-L and C9-S. Results: Investigation of expression of C9-L and C9-S demonstrated distinct biochemical profiles, region-specific changes, and distinct subcellular localizations in ALS tissues. In particular, C9-L antibody exhibited a diffuse cytoplasmic staining in neurons and labeled large speckles in cerebellar Purkinje cells. In contrast, C9-S antibody gave very specific labeling of the nuclear membrane in healthy neurons, with apparent relocalization to the plasma membrane of diseased motor neurons in ALS. Coimmunoprecipitation experiments revealed an interaction of the C9-isoforms with both Importin b1 and Ran-GTPase, components of the nuclear pore complex. Interpretation: Using these antibodies, we have shown that C9orf72 may be involved in nucleocytoplasmic shuttling and this may have relevance to pathophysiology of ALS/FTLD. Our antibodies have provided improved detection of C9orf72 protein isoforms, which will help elucidate its physiological function and role in ALS/FTLD. ANN NEUROL 2015;78:568-583 H exanucleotide (G 4 C 2 ) repeat expansions within a noncoding region of C9orf72 are the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), accounting for up to 50% of ALS, 29% of FTLD, and 88% of ALS/ FTLD patients, including familial and sporadic cases.

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“…These differences could be the consequence of a species-specific tolerance to the deprivation of C9ORF72 homologues or could be the result of dissimilar methods used to decrease the expression of C9ORF72, such as genetic knockdown versus the use of ASOs. A description of a patient carrying a homozygous C9ORF72 repeat expansion who did not show a more severe phenotype suggests that the loss-offunction hypothesis for C9 pathogenesis is less probable or, at least, not the predominant mechanism [33]. The function of the C9ORF72 gene is still largely unknown, so despite the In yellow: antisense oligonucleotide (ASO) therapy is able to act either by regulating splicing or by regulating translation with an RNAse H-dependent pathway or via steric block.…”

Section: Introductionmentioning

confidence: 99%

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

et al. 2016

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The identification of the hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene as the most frequent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened the path for advances in the knowledge and treatment of these disorders, which remain incurable. Recent evidence suggests that HRE RNA can cause gain-of-function neurotoxicity, but haploinsufficiency has also been hypothesized. In this review, we describe the recent developments in therapeutic targeting of the pathological expansion of C9ORF72 for ALS, FTD, and other neurodegenerative disorders. Three approaches are prominent: (1) an antisense oligonucleotides/RNA interference strategy; (2) using small compounds to counteract the toxic effects directly exerted by RNA derived from the repeat transcription (foci), by the translation of dipeptide repeat proteins (DPRs) from the repeated sequence, or by the sequestration of RNA-binding proteins from the C9ORF72 expansion; and (3) gene therapy, not only for silencing the toxic RNA/protein, but also for rescuing haploinsufficiency caused by the reduced transcription of the C9ORF72 coding sequence or by the diminished availability of RNA-binding proteins that are sequestered by RNA foci. Finally, with the perspective of clinical therapy, we Maria Sara Cipolat Mis and Simona Brajkovic contributed equally to this work.

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Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia

Cited by 125 publications

References 32 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

Isoform‐specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

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