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Acta Neuropathologica

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01.03.2014 | Review

Mechanisms of toxicity in C9FTLD/ALS

verfasst von: Tania F. Gendron, Veronique V. Belzil, Yong-Jie Zhang, Leonard Petrucelli

Erschienen in: Acta Neuropathologica | Ausgabe 3/2014

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Abstract

A hexanucleotide repeat expansion within a non-coding region of the C9ORF72 gene is the most common mutation causative of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Elucidating how this bidirectionally transcribed G₄C₂·C₄G₂ expanded repeat causes “C9FTLD/ALS” has since become an important goal of the field. Likely pathogenic mechanisms include toxicity induced by repeat-containing RNAs, and loss of C9orf72 function due to epigenetic changes resulting in decreased C9ORF72 mRNA expression. With regards to the former, sense and antisense transcripts of the expanded repeat aberrantly interact with various RNA-binding proteins and form discrete nuclear structures, termed RNA foci. These foci have the capacity to sequester select RNA-binding proteins, thereby impairing their function. (G₄C₂)_exp and (C₄G₂)_exp transcripts also succumb to an alternative fate: repeat-associated non-ATG (RAN) translation. This unconventional mode of translation, which occurs in the absence of an initiating codon, results in the abnormal production of poly(GA), poly(GP), poly(GR), poly(PR) and poly(PA) peptides, collectively referred to as C9RAN proteins. C9RAN proteins form neuronal inclusions throughout the central nervous system of C9FTLD/ALS patients and may contribute to disease pathogenesis. This review aims to summarize the important findings from studies examining mechanisms of disease in C9FTLD/ALS, and will also highlight some of the many questions in need of further investigation.

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Titel: Mechanisms of toxicity in C9FTLD/ALS
verfasst von: Tania F. Gendron
Veronique V. Belzil
Yong-Jie Zhang
Leonard Petrucelli
Publikationsdatum: 01.03.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 3/2014
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-013-1237-z

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Mechanisms of toxicity in C9FTLD/ALS

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