RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia

作者：Tao Zu, Yuanjing Liu, Mónica Báñez-Coronel, Tammy Reid, Olga Pletniková, Jada Lewis, Timothy M. Miller, Matthew B. Harms, Annet E. Falchook, S. H. Subramony, Lyle W. Ostrow, Jeffrey D. Rothstein, Juan C. Troncoso, Laura P.W. Ranum · 发表于：Proceedings of the National Academy of Sciences · 年份：2013 · DOI：10.1073/pnas.1315438110 · 被引用次数：793 · 研究领域：Amyotrophic Lateral Sclerosis Research、Neurogenetic and Muscular Disorders Research、Genetic Neurodegenerative Diseases

The finding that a GGGGCC (G4C2) hexanucleotide repeat expansion in the chromosome 9 ORF 72 (C9ORF72) gene is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) links ALS/FTD to a large group of unstable microsatellite diseases. Previously, we showed that microsatellite expansion mutations can be bidirectionally transcribed and that these mutations express unexpected proteins by a unique mechanism, repeat-associated non-ATG (RAN) translation. In this study, we show that C9ORF72 antisense transcripts are elevated in the brains of C9ORF72 expansion-positive [C9(+)] patients, and antisense GGCCCC (G2C4) repeat-expansion RNAs accumulate in nuclear foci in brain. Additionally, sense and antisense foci accumulate in blood and are potential biomarkers of the disease. Furthermore, we show that RAN translation occurs from both sense and antisense expansion transcripts, resulting in the expression of six RAN proteins (antisense: Pro-Arg, Pro-Ala, Gly-Pro; and sense: Gly-Ala, Gly-Arg, Gly-Pro). These proteins accumulate in cytoplasmic aggregates in affected brain regions, including the frontal and motor cortex, hippocampus, and spinal cord neurons, with some brain regions showing dramatic RAN protein accumulation and clustering. The finding that unique antisense G2C4 RNA foci and three unique antisense RAN proteins accumulate in patient tissues indicates that bidirectional transcription of expanded alleles is a fundamental pathologic feature of C9ORF...