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

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• 作者：Peter E.A. Ash¹ ; ³ ; ⁴ ; Kevin F. Bieniek¹ ; ³ ; ⁴ ; Tania F. Gendron¹ ; Thomas Caulfield¹ ; Wen-Lang Lin¹ ; Mariely DeJesus-Hernandez¹ ; ³ ; Marka M. van Blitterswijk¹ ; Karen Jansen-West¹ ; Joseph W. Paul III¹ ; Rosa Rademakers¹ ; Kevin B. Boylan² ; Dennis W. Dickson¹ ; Leonard Petrucelli¹ ; ^{petrucelli.leonard@mayo.edu}
• 刊名：Neuron
• 出版年：2013
• 出版时间：20 February, 2013
• 年：2013
• 卷：77
• 期：4
• 页码：639-646
• 全文大小：1387 K

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Summary

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¡ªrepeat-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.