Defective RNA metabolism in motor neurons from Amyotrophic Lateral Scelosis patients

2012 Fiscal Year Final Research Report

• Project/Area Number: 23700455
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: TSUIJI Hitomi 独立行政法人理化学研究所, 運動ニューロン変性研究チーム, 研究員 (40455358)
• Project Period (FY): 2011 – 2012
• Keywords: ALS / spliceosome / snRNP / TDP-43 / RNA

Research Abstract

Neurodegenerative diseases are characterized by the death of specific type of neurons. The motor neuron diseases amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are caused by dysfunction of TDP-43, RNA-binding protein and SMN, essential for biogenesis of spliceosomal component snRNPs, respectively. However, the defects in RNA metabolism common to these diseases remain unclear. We show that TDP-43 localizes in nuclear gems through association with the SMN complex, and is involved in spliceosome maintenance. Moreover, gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in the nuclei of ALS motor neurons but not in the temporal lobe of FTLD with TDP-43 pathology. Together, these findings indicate that collapse of spliceosome stability is the critical process common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons.

Research Products

• [Journal Article] Spliceosome integrity is defective in motor neuron disease ALS and SMA (2013)
  • Author(s): Tsuiji H., Iguchi Y., Furuya A., Kataoka A., Hatsuta H., Atsuta N., Tanaka F., Hashizume Y., Akatsu H., Murayama S., Sobue G., Yamanaka K
  • Journal Title: EMBO Molecular Medicine Volume: 5(2) Pages: 221-34
  • Peer Reviewed
• [Presentation] 運動神経変性疾患に共通するスプライシング経路の破たん (2013)
  • Author(s): 築地仁美
  • Place of Presentation: 京都大学医学部(京都)
  • Year and Date: 2013-01-25
• [Presentation] 遺伝性ALS モデルにおけるSIRT1 の関与 (2012)
  • Author(s): 永津真司、築地仁美、木下専、三澤日出巳、山中宏二
  • Organizer: 第85回日本生化学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20121200
• [Presentation] Spliceosome integrity is defective in motor neuron disease ALS and SMA (2012)
  • Author(s): Tsuiji H., Iguchi Y., Furuya A., Kataoka A., Hatsuta H., Atsuta N., Tanaka F., Hashizume Y., Akatsu H., Murayama S., Sobue G., Yamanaka K
  • Organizer: Cold Spring Harbor Meeting : Neurodegenerative Disorders
  • Place of Presentation: Cold Spring Harbor/NY/USA
  • Year and Date: 20121100
• [Presentation] Spliceosome Integrity is a Common Target for Motor Neuron Disease (2012)
  • Author(s): Tsuiji H. and Yamanaka K
  • Organizer: 第35回日本神経科学大会シンポジウム : RNA 結合蛋白質と病態
  • Place of Presentation: 名古屋
  • Year and Date: 20120900
• [Presentation] 運動神経変性疾患に共通するスプライソソーム異常 (2012)
  • Author(s): 築地仁美、井口洋平、古屋亜佐子、片岡礼音、村山繁雄、祖父江元、山中宏二
  • Organizer: 第14回RNA学会年会
  • Place of Presentation: 仙台(口頭発表)
  • Year and Date: 20120700
• [Presentation] TDP-43 maintains proper U snRNA levels through association with SMN in Cajal/Gem body (2012)
  • Author(s): Tsuiji H., Iguchi Y., Furuya A., Kataoka A., Atsuta N., Tanaka F., Sobue G., Yamanaka K
  • Organizer: Keystone Symposia on Molecular and Cellular Biology : Protein-RNA Interaction in Biology and Disease
  • Place of Presentation: Santa Fe, New Mexico/USA
  • Year and Date: 20120304-06
• [Presentation] Integrity fo Spliceosome is a Common Target for Motor Neuron Disease (2012)
  • Author(s): Tsuiji H
  • Organizer: 第1回国際若手シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2012-11-17
• [Presentation] U snRNP形成における筋萎縮性側索硬化症(ALS)原因遺伝子TDP-43 の役割 (2011)
  • Author(s): 築地仁美、片岡礼音、山中宏二
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜(口頭発表)
  • Year and Date: 20111200
• [Presentation] Regulation of spliceosome by ALS-causative gene TDP-43 (2011)
  • Author(s): Tsuiji H., Kataoka A., Yamanaka K
  • Organizer: 第34回日本神経科学大会
  • Place of Presentation: 横浜(口頭発表)
  • Year and Date: 20110900
• [Presentation] A Role of TDP-43 in Regulation of U snRNP Formation (2011)
  • Author(s): Tsuiji H., Kataoka A., Yamanaka K
  • Organizer: Cold Spring Harbor Laboratory Meeting: Eukaryotic mRNA Processing
  • Place of Presentation: Cold Spring Harbor, New York, USA
  • Year and Date: 20110823-27
• [Presentation] A Role of TDP-43 in The Regulation of spliceosomal U snRNPs (2011)
  • Author(s): Tsuiji H., Kataoka A., Yamanaka K
  • Organizer: The 16^<th> Annual Meeting of the RNA Society and The 13th Annual Meeting of the RNA Society of Japan
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20110614-18