期刊
NEURON
卷 77, 期 4, 页码 639-646出版社
CELL PRESS
DOI: 10.1016/j.neuron.2013.02.004
关键词
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资金
- Mayo Clinic Foundation
- National Institutes of Health/National Institute on Aging [R01 AG026251, P01 AG003949, P50 AG016574]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R21 NS074121-01, R01 NS080882, R01 NS063964, R01 NS077402, P50 NS72187]
- National Institute of Environmental Health Services [R01 ES20395]
- Amyotrophic Lateral Sclerosis Association
- ALS Therapy Alliance
- Department of Defense [W81XWH-10-1-0512-1, W81XWH-09-1-0315AL093108]
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 GAG 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.
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