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

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

来源：Neuron, 2013, 77(4): 639-646.

DOI：10.1016/j.neuron.2013.02.004

• FRONTOTEMPORAL LOBAR DEGENERATION
• AMYOTROPHIC-LATERAL-SCLEROSIS
• HEXANUCLEOTIDE REPEAT EXPANSION
• RNA
• INCLUSIONS
• DISORDERS
• SPECTRUM
• FTD
• ALS

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.

• 出版日期2013-2-20