Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS

Peter E.A. Ash, Kevin F. Bieniek, Tania F. Gendron, Thomas Caulfield, Wen Lang Lin, Mariely DeJesus-Hernandez, Marka M. Van Blitterswijk, Karen Jansen-West, Joseph W. Paul, Rosa Rademakers, Kevin B. Boylan, Dennis W. Dickson, Leonard Petrucelli

Research output: Contribution to journalArticle

604 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)639-646
Number of pages8
JournalNeuron
Volume77
Issue number4
DOIs
StatePublished - Feb 20 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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