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Molecular and Cellular Adaptation(Cooperating field)Neuroscience and Pathobiology


The molecular mechanisms for neurodegenerative diseases such as motor neuron disease (amyotrophic lateral sclerosis, ALS) and Alzheimer's disease remain unknown. Therefore, therapeutic strategy has not been established. Our laboratory aims to elucidate the mechanism of onset and progression of motor neuron disease, which have been shown to be derived from the pathological changes within different cell types; motor neurons and glial cells. We will analyze inherited ALS, using mouse, cell culture, and in vitro system as models. Based on these studies, we expect to design the therapeutic interventions for the sporadic neurodegenerative diseases.

Research Projects

  1. Studies on neuroinflammation in ALS and Alzheimer's disease
  2. Studies on M1-, M2- conversion of microglia
  3. Studies on TGF-β1 as a regulator of ALS pathology
  4. Studies on TDP-43 (ALS10)

Faculty Members

YAMANAKA Koji M.D., Ph.D. Professor Department of Neuroscience and Pathobiology
KOMINE Okiru Ph.D. Assistant Professor Department of Neuroscience and Pathobiology
WATANABE Seiji Ph.D. Assistant Professor Department of Neuroscience and Pathobiology
ENDO Fumito M.D., Ph.D. Designated assistant Professor Department of Neuroscience and Pathobiology


  • 2016
    1. Watanabe S, Ilieva H, Tamada H, Nomura H, Komine O, Endo F, Jin S, Mancias P, Kiyama H, Yamanaka K. Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO Mol Med, 2016; in press.
    2. Lasiene J, Komine O, Fujimori-Tonou N, Powers B, Endo F, Watanabe S, Shijie J, Ravits J, Horner P, Misawa H, Yamanaka K. Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons. Acta Neuropathol Commun, 2016; 4: 15.
    3. Chhangani D, Endo F, Amanullah A, Upadhyay A, Watanabe S, Mishra R, Yamanaka K, Mishra A. Mahogunin ring finger 1 confers cytoprotection against mutant SOD1 aggresomes and is defective in an ALS mouse model. Neurobiol Dis, 2016; 86: 16-28.
  • 2015
    1. Endo F, Komine O, Fujimori-Tonou N, Katsuno M, Jin S, Watanabe S, Sobue G, Dezawa M, Wyss-Coray T, Yamanaka K. Astrocyte-derived TGF-beta1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells. Cell Rep, 2015; 11: 592-604.
    2. Heneka MT, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP. Neuroinflammation in Alzheimer’s disease. Lancet Neurol, 2015; 14: 388-405.
  • 2014
    1. Watanabe S, Hayakawa T, Wakasugi K, Yamanaka K. Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity. Cell Death Dis, 2014; 5: e1497.
    2. Watanabe S, Ageta-Ishihara N, Nagatsu S, Takao K, Komine O, Endo F, Miyakawa T, Misawa H, Takahashi R, Kinoshita M, Yamanaka K. SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system. Molecular Brain, 2014; 7: 62.
    3. Nomura T, Watanabe S, Kaneko K, Yamanaka K, Nukina N, Furukawa Y. Intranuclear aggregation of mutant FUS/TLS as a molecular pathomechanism of amyotrophic lateral sclerosis. J Biol Chem, 2014; 289: 1192-1202.
    4. Austin JA, Wright GS, Watanabe S, Grossmann JG, Antonyuk SV, Yamanaka K, Hasnain SS. Disease causing mutants of TDP-43 nucleic acid binding domains are resistant to aggregation and have increased stability and half-life. Proc Natl Acad Sci U S A, 2014.
  • 2013
    1. Watanabe S, Kaneko K, Yamanaka K. Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins. J Biol Chem, 2013; 288: 3641-3654.
    2. Tsuiji H, Iguchi Y, Furuya A, Kataoka A, Hatsuta H, Atsuta N, Tanaka F, Hashizume Y, Akatsu H, Murayama S, Sobue G, Yamanaka K. Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol Med, 2013; 5: 221-234.
    3. Toichi K, Yamanaka K, Furukawa Y. Disulfide scrambling describes the oligomer formation of superoxide dismutase (SOD1) proteins in the familial form of amyotrophic lateral sclerosis. J Biol Chem, 2013; 288: 4970-4980.
    4. Mishra A, Maheshwari M, Chhangani D, Fujimori-Tonou N, Endo F, Joshi AP, Jana NR, Yamanaka K. E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity. Neurobiol Aging, 2013; 34: 1310 e1311-1323.
    5. Iguchi Y, Katsuno M, Niwa J-I, Takagi S, Ishigaki S, Ikenaka K, Kawai K, Watanabe H, Yamanaka K, Takahashi R, Misawa H, Sasaki S, Tanaka F, Sobue G. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain : a journal of neurology, 2013; 136: 1371-1382.
  • 2011
    1. Lasiene J, Yamanaka K. Glial cells in amyotrophic lateral sclerosis. Neurology research international, 2011; 2011: 718987-718987.
  • 2008
    1. Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature neuroscience, 2008; 11: 251-253.
    2. Yamanaka K, Boillee S, Roberts EA, Garcia ML, McAlonis-Downes M, Mikse OR, Cleveland DW, Goldstein LSB. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proceedings of the National Academy of Sciences of the United States of America, 2008; 105: 7594-7599.
  • 2006
    1. Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW. Onset and Progression in Inherited ALS determined by Motor Neurons and Microglia. Science, 2006; 312: 1389-1392.

Research Keywords

amyotrophic lateral sclerosis (ALS)、 Alzheimer's disease、 neurodegenerative diseases、 neuron、 microglia、 astrocyte、 neuroinflammation、 SOD1、 TDP-43