Elucidation of the physiological function of ALS2 and mechanism for motor neuron degeneration through the identification of ALS2 activators

2009 Fiscal Year Final Research Report

• Project/Area Number: 19500330
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokai University
• Principal Investigator: HADANO Shinji Tokai University, 医学部, 准教授 (60281375)
• Project Period (FY): 2007 – 2009
• Keywords: 分子 / 細胞 / 神経生物学

Research Abstract

Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of progressive neurodegenerative disorders characterized by a selective loss of motor neurons in the cerebral cortex, brainstem, and spinal cord. Currently, the mechanism for the selective degeneration of motor neurons is unclear. We focus on the newly-identified ALS causative gene product, called ALS2, and investigate the molecular function of ALS2 and its activators. We here identified Rac1 as a novel ALS2 activator, and revealed that ALS2 plays a role in macropinocytosis and endosome fusion in cells. Our study will contribute to,define the molecular mechanisms underlying the neuronal dysfunction and degeneration in ALS.

Research Products

• [Journal Article] Loss of ALS2/alsin exacerbates motor dysfunction in a SOD1H46R-expressing ALS mouse model by disturbing endolysosomal trafficking (2010)
  • Author(s): Hadano S, Otomo A, Kunita R, Suzuki-Utsunomiya K, Akatsuka A, Koike M, Aoki M, Uchiyama Y, Itoyama Y, Ikeda JE
  • Journal Title: PLoS ONE 5 Pages: e9805
  • Peer Reviewed
• [Journal Article] Natural history of young-adult amyotrophic lateral sclerosis (2009)
  • Author(s): Yoshii Y, Hadano S, Otomo A, Suzuki K, Ikeda K, Ikeda JE, Iwasaki Y
  • Journal Title: Neurology 73 Pages: 648-649
  • Peer Reviewed
• [Journal Article] A dopamine receptor antagonist L-745, 870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice (2008)
  • Author(s): Tanaka K, Okada Y, Kanno T, Otomo A, Yanagisawa Y, Shouguchi-Miyata J, Suga E, Kohiki E, Onoe K, Osuga H, Aoki M, Hadano S, Itoyama Y, Ikeda JE
  • Journal Title: Exp Neurol 211 Pages: 378-386
  • Peer Reviewed
• [Journal Article] ALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth (2008)
  • Author(s): Otomo A, Kunita R, Suzuki-Utsunomiya K, Mizumura H, Onoe K, Osuga H, Hadano S, Ikeda JE
  • Journal Title: Biochem Biophys Res Commn 370 Pages: 87-92
  • Peer Reviewed
• [Journal Article] Molecular and cellular function of ALS2/alsin: Implication of membrane dynamics in neuronal development and degeneration (2007)
  • Author(s): Hadano S, Kunita R, Otomo A, Suzuki-Utsunomiya K, Ikeda JE
  • Journal Title: Neurochem Int 51 Pages: 74-84
  • Peer Reviewed
• [Journal Article] ALS2CL, a novel ALS2-interactor, modulates ALS2-mediated endosome dynamics (2007)
  • Author(s): Suzuki-Utsunomiya K, Hadano S, Otomo A, Kunita R, Mizumura H, Osuga H, Ikeda JE
  • Journal Title: Biochem Biophys Res Commn 354 Pages: 491-497
  • Peer Reviewed
• [Journal Article] The Rab5 activator ALS2/alsin acts as a novel Rac1 effector through Rac1-activated endocytosis (2007)
  • Author(s): Kunita R, Otomo A, Mizumura H, Suzuki-Utsunomiya K, Hadano S, Ikeda JE
  • Journal Title: J Biol Chem 282 Pages: 16599-16611
  • Peer Reviewed
• [Presentation] ALS2/alsin, a Rab5 guanine nucleotide exchange factor, acts as a regulator for autophagosomalendolysosomal protein degradation. Keystone Symposia, Cell Death Pathway (2010)
  • Author(s): Hadano S, Otomo A, Kunita R, Suzuki-Utsunomiya K, Akatsuka A, Koike M, Aoki M, Uchiyama Y, Itoyama Y, Ikeda JE
  • Organizer: Apoptosis, Autophagy and Necrosis (X3)
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 20100312-20100317
• [Presentation] Loss of Rac1-induced macropinosomal and endosomal localization of ALS2 underlies the pathogenesis for motor neuron diseases caused by missense mutations in the ALS2 gene (2009)
  • Author(s): Otomo A, Kunita R, Suzuki-Utsunomiya K, Ikeda JE, Hadano S
  • Organizer: 20th International Symposium on ALS/MND
  • Place of Presentation: Berlin, Germany
  • Year and Date: 20091208-20091210
• [Presentation] Generation and characterization of congenic lines of mutant SOD1 transgenic and Als2 knockout mice (2009)
  • Author(s): Hadano S, Otomo A, Kunita R, Suzuki-Utsunomiya K, Yoshii Y, Aoki M, Itoyama Y, Iwasaki Y, Ikeda JE
  • Organizer: 20th International Symposium on ALS/MND
  • Place of Presentation: Berlin, Germany
  • Year and Date: 20091208-20091210
• [Presentation] 筋萎縮性側索硬化症/運動ニューロン疾患研究の新展開. -オートファジーとエンドゾーム動態との関連について- (2009)
  • Author(s): 秦野伸二
  • Organizer: Cell Biology Summer Meeting 2009 (CBSM2009)
  • Place of Presentation: つくば
  • Year and Date: 20090711-20090712
• [Presentation] Loss of Rac1- mediated macropinosomal recruitment of ALS2/alsin underlies the pathogenesis for motor neuron disease caused by missense mutations in the ALS2 gene. BMB2008 (2008)
  • Author(s): Otomo A, Kunita R, Suzuki-Utsunomiya K, Hadano S, Ikeda JE
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会、合同大会
  • Place of Presentation: 神戸
  • Year and Date: 20081209-20091212
• [Presentation] ALS2/alsin-deficient SOD1H46R transgenic mice exhibit increased insoluble proteins in the spinal cord (2008)
  • Author(s): Hadano S, Otomo A, Kunita R, Suzuki-Utsunomiya K, Onoe K, Osuga H, Aoki M, Itoyama Y, Ikeda JE
  • Organizer: 19th International Symposium on ALS/MND
  • Place of Presentation: Birmingham, U.K.
  • Year and Date: 20081103-20081105
• [Presentation] Loss of ALS2/alsin exacerbates motor dysfunction and axonal damage in SOD1H46R transgenic mice (2008)
  • Author(s): Hadano S, Otomo A, Kunita R, Suzuki-Utsunomiya K, Onoe K, Osuga H, Aoki M, Itoyama Y, Ikeda JE
  • Organizer: 第51回日本神経化学会
  • Place of Presentation: 富山
  • Year and Date: 20080911-20080913
• [Presentation] The Rab5 activator ALS2/alsin acts as a novel Rac1 effector via Rac1-activated macropinocytosis (2007)
  • Author(s): Kunita R, Otomo A, Mizumura H, Suzuki-Utsunomiya K, Hadano S, Ikeda JE
  • Organizer: 第50回日本神経化学会
  • Place of Presentation: 横浜
  • Year and Date: 20070910-20070912
• [Presentation] The Rab5 activator ALS2/alsin acts as a novel Rac1 effector through Rac1-activated macropinocytosis (2007)
  • Author(s): Kunita R, Otomo A, Mizumura H, Suzuki-Utsunomiya K, Hadano S, Ikeda JE
  • Organizer: Human Genome Meeting 2007
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20070521-20070524
• [Presentation] ALS2/alsin is localized to endosomes in primary cultured hippocampal neurons and implicated in axon elongation (2007)
  • Author(s): Otomo A, Kunita R, Suzuki-Utsunomiya K, Mizumura H, Onoe K, Osuga H, Hadano S, Ikeda JE
  • Organizer: Human Genome Meeting 2007
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20070521-20070524