• Top page
  • Timetable
  • Per session
  • Per presentation
  • How to
  • Meeting Planner



Brain Proteinopathy 2014
Brain Proteinopathy 2014

開催日 2014/9/11
時間 17:00 - 19:00
会場 Room E(301)
Chairperson(s) 田中 元雅 / Motomasa Tanaka (独立行政法人理化学研究所 脳科学総合研究センター タンパク質構造疾患研究チーム / Laboratory for Protein Conformation Diseases, RIKEN Brain Science Institute, Japan)
貫名 信行 / Nobuyuki Nukina (順天堂大学大学院医学研究科 神経変性疾患病態治療探索講座 / Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Japan)

FTLD/ALS causing C9orf72 intronic hexanucleotide repeat is translated into aggregating dipeptide repeat proteins

  • S1-E-3-3
  • Kohji Mori:1 
  • 1:Adolf Butenandt-Institute, Ludwig-Maximilians University Munich, Germany 

Genetic mutations causing familial variants of a neurodegenerative disease are often associated with the genes encoding the proteins found in deposits. Followed by the identification of TDP-43 as a major component of protein aggregates in frontotemporal lober degeneration (FTLD) and its genetic mutations as a cause of familial amyotrophic lateral sclerosis (ALS), a set of genes have been identified as a genetic cause or disease modifier of FTLD and/or ALS. Among them, pathological GGGGCC repeat expansion in intron/promoter region of C9orf72 was identified in 2011 as a most common genetic cause of FTLD and amyotrophic lateral sclerosis (ALS) in western population. How the repeat causes neurodegeneration is currently under intensive investigation. Most patients with C9orf72 repeat expansion show TDP-43 pathology but the pathology is not restricted to TDP-43. There are abundant p62-positive/TDP-43-negative inclusions and they are even more frequent than TDP-43-positive inclusions. However, the major component of the p62-positive inclusions was enigmatic. We have recently found that the RNA transcript from the GGGGCC repeat DNA could be translated in ATG-independent manner. The unconventional translation produces 3 different dipeptide repeat (DPR) proteins in each reading frames from the RNA repeat transcript, namely poly Glycine-Alanine (GA), poly Glycine-Proine (GP) and poly Glycine-Arginine (GR). These DPR proteins are selectively accumulated in the brain of C9orf72 repeat expansion carriers, but not in that of control cases, non-C9orf72 related FTLD/ALS cases and GAG repeat-related Huntington disease cases. In addition antisense strand CCCCGG repeat-derived RNA transcritpt is also translated in non-ATG dependent manner, resulting in accumulation of poly Alanine-Proline (AP), poly Proline-Arginine (PR) and again poly GP. These DPR protein species are co-aggregating with each other and co-localized with p62 in C9orf72 patient brain tissue. Thus, the disease causing intronic hexanucleotide repeat is bidirectionally transcribed and translated into five distinct DPR proteins that forms characteristic inclusions in C9orf72 repeat expansion carriers.

Copyright © Neuroscience2014. All Right Reserved.