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Neuron. 2013 Feb 20;77(4):639-46. doi: 10.1016/j.neuron.2013.02.004. Epub 2013 Feb 12.

Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS.

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1
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.

Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders with clinical, genetic, and neuropathological overlap. Hexanucleotide (GGGGCC) repeat expansions in a noncoding region of C9ORF72 are the major genetic cause of FTD and ALS (c9FTD/ALS). The RNA structure of GGGGCC repeats renders these transcripts susceptible to an unconventional mechanism of translation-repeat-associated non-ATG (RAN) translation. Antibodies generated against putative GGGGCC repeat RAN-translated peptides (anti-C9RANT) detected high molecular weight, insoluble material in brain homogenates, and neuronal inclusions throughout the CNS of c9FTD/ALS cases. C9RANT immunoreactivity was not found in other neurodegenerative diseases, including CAG repeat disorders, or in peripheral tissues of c9FTD/ALS. The specificity of C9RANT for c9FTD/ALS is a potential biomarker for this most common cause of FTD and ALS. These findings have significant implications for treatment strategies directed at RAN-translated peptides and their aggregation and the RNA structures necessary for their production.

PMID:
23415312
PMCID:
PMC3593233
DOI:
10.1016/j.neuron.2013.02.004
[Indexed for MEDLINE]
Free PMC Article
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