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

演題詳細

Symposium

神経発生と疾患におけるRNA制御機構
RNA regulation in neural development and diseases

開催日 2014/9/11
時間 14:00 - 16:00
会場 Room E(301)
Chairperson(s) 河原 行郎 / Yukio Kawahara (大阪大学大学院医学系研究科遺伝子機能制御学 / Osaka University, Graduate School of Medicine, Japan)
築地 仁美 / Hitomi Tsuiji (名古屋市立大学大学院薬学研究科 病態生化学分野 / Department of Biomedical Science, Nagoya City University, Graduate School Pharmaceutical Science, Japan)


High-throughput Genetic Screens to Define Mechanisms of Neurodegenerative Diseases

  • S1-E-2-4
  • Aaron Gitler:1 
  • 1:Stanford University, USA 

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS cause some forms of ALS. We discovered that TDP-43 and FUS harbor prion-like domains (Cushman et al. 2010, Gitler and Shorter 2011, King et al. 2012). There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics analyses to predict prion-like domains in a subset of them. We have been sequencing some of these genes, including TAF15 and EWSR1, in ALS patients and identified missense variants, which were absent in a large number of healthy controls (Couthouis et al. 2011, Couthouis et al. 2012). We propose that RNA binding proteins with prion-like domains might contribute very broadly to pathogenesis of ALS and related neurodegenerative diseases (Kim et al. 2013) and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate disease gene discovery.

My laboratory has used the yeast model system to define the mechanisms by which TDP-43 and FUS contribute to ALS. These yeast models recapitulate several salient features, including TDP-43 cytoplasmic aggregation and cytotoxicity. We have leveraged this simple model system to make several fundamental discoveries into the role of TDP-43 and FUS in neurodegeneration. These discoveries include mechanistic insight into what drives TDP-43 and FUS aggregation and cytotoxicity (Johnson et al. 2008, Sun et al. 2011), a mechanism to explain how ALS-linked TDP-43 mutations affect the protein and contribute to disease (Johnson et al. 2009), the discovery of novel genetic contributors to human ALS, including one of the most common genetic risk factors, ataxin 2 intermediate-length polyQ expansions (Elden et al. 2010, Hart et al. 2012, Hart and Gitler 2012), and even an unexpected and novel therapeutic target for ALS, lariat debranching enzyme (Armakola et al. 2012).

Copyright © Neuroscience2014. All Right Reserved.