title: Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS.
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.
authors: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors: Peter E A
authors: PE
authors: Ash
authors: Kevin F
authors: KF
authors: Bieniek
authors: Tania F
authors: TF
authors: Gendron
authors: Thomas
authors: T
authors: Caulfield
authors: Wen-Lang
authors: WL
authors: Lin
authors: Mariely
authors: M
authors: Dejesus-Hernandez
authors: Marka M
authors: MM
authors: van Blitterswijk
authors: Karen
authors: K
authors: Jansen-West
authors: Joseph W
authors: JW
authors: Paul
authors: Rosa
authors: R
authors: Rademakers
authors: Kevin B
authors: KB
authors: Boylan
authors: Dennis W
authors: DW
authors: Dickson
authors: Leonard
authors: L
authors: Petrucelli
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D002899:Chromosomes, Human, Pair 9 / Q000378:metabolism*; D042622:DNA Repeat Expansion / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D005838:Genotype; D006801:Humans; D010455:Peptides / Q000235:genetics*
chemical_list: D010455:Peptides