Common defects of RNA metabolism in motor neuron diseases SMA and ALS

2016 Fiscal Year Final Research Report

• Project/Area Number: 25430055
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Nagoya City University (2014-2016); Institute of Physical and Chemical Research (2013)
• Principal Investigator: Tsuiji Hitomi 名古屋市立大学, 大学院薬学研究科, 講師 (40455358)
• Co-Investigator(Renkei-kenkyūsha): YAMANAKA Koji 名古屋大学, 環境医学研究所, 教授 (80446533)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Keywords: 運動ニューロン / ALS / SMA / スプライソソーム / TDP-43 / FUS / SMN / スプライシング

Outline of Final Research Achievements

Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei. This aberrant accumulation of U snRNAs in ALS motor neurons indicates both ALS and SMA motor neurons have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons.

Free Research Field

病態神経科学、分子生物学