Laboratories

Neuroscience and Pathobiology

KEYWORDS

  • DNA repair
  • Genome instability
  • Genetic disorder
  • Cancer
  • Genomics
  • Proteomics
  • Molecular biology
  • Human genetics  

HEAD

YAMANAKA Koji

Professor

Researchers

LAB MEMBER

Faculty Position Researchers
KOMINE Okiru Lecturer Researchers
ENDO Fumito Designated Lecturer Researchers
KAWADE Noe Designated assistant Professor Researchers
SHINNO Kanako Designated assistant Professor Researchers
HORIUCHI Mai Designated assistant Professor Researchers
MAEKAWA Kasumi Designated assistant Professor Researchers

CONTACT

Email mnd◎riem.nagoya-u.ac.jp (Please send a message after replacing "◎" mark with "@" mark. )
HP Private Page

OUTLINE

Despite significant advances in identifying causative genes for neurodegenerative diseases, the majority of patients with amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD)—the primary focus of our laboratory—develop sporadic, non-hereditary forms. Therefore, the fundamental questions regarding the pathogenic mechanisms remain unanswered: why do neurons degenerate, and how does the disease progress from initial molecular perturbations to clinical manifestation?

Our laboratory's pioneering work has established that motor neuron degeneration in ALS is not solely driven by cell-intrinsic defects, but also by ""non-cell autonomous"" mechanisms actively mediated by surrounding glial cells. Building on this foundation, our research program integrates both neuron-intrinsic and extrinsic perspectives to elucidate neurodegenerative mechanisms and translate these insights into novel therapeutic strategies.

In our ALS research, we investigate how abnormalities in disease-causing proteins such as TDP-43, coupled with organelle dysfunction including mitochondria and ER impairment, trigger motor neuron degeneration. Critically, we examine how these neuronal defects propagate disease pathology through glial cells—particularly microglia and astrocytes—thereby accelerating disease progression.

Our AD research complements this approach by focusing on neuroinflammation and brain environment alterations driven by glial responses to pathogenic protein accumulation (amyloid-β and tau). We seek to identify the molecular and cellular mechanisms governing disease onset and progression, with particular emphasis on key neuroinflammatory regulators as potential therapeutic targets.

Through integrated studies using disease model mice and in vitro systems including iPS cells, we aim to comprehensively map the pathogenic cascade—from initial molecular perturbations within neurons, through brain environment disruption, to ultimate neurodegeneration. Our ultimate goal is to develop novel therapeutic interventions for neurodegenerative diseases.

RESEARCH PROJECTS

  1. Elucidation of ALS and AD Pathogenesis Targeting Neuroinflammation and Microglial Activity Regulation
  2. Molecular Pathology of Astrocytes in AD and ALS
  3. Neurodegenerative Mechanisms Involving Oligodendrocytes and White Matter Pathology
  4. Molecular mechanisms of TDP-43 induced neurodegeneration
  5. Elucidating the Significance of Organelle Interconnection Failure in Neurodegeneration

BIBLIOGRAPHY

2025
  1. Watanabe S, Yamanaka K: Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases. Bioessays 4: e70016, 2025.
  2. Maekawa K, Sobue A, Komine O, Saito Y, Murayama S, Saido TC, Saito T, Yamanaka K: Long-term systemic androgen deprivation partially modulates neuroinflammation in male AppNL-G-F/NL-G-F mice. Scientific Reports 15: 14702, 2025.
2024
  1. Horiuchi M, Watanabe S, Komine O, Takahashi E, Kaneko K, Itohara S, Shimada M, Ogi T, Yamanaka K: ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice. Acta Neuropathologica Communications 12: 184, 2024.
  2. Sobue A, Komine O, Endo F, Kakimi C, Miyoshi Y, Kawade N, Watanabe S, Saito Y, Murayama S, Saido SC, Saito T, Yamanaka K: Microglial cannabinoid receptor type II stimulation improves cognitive impairment and neuroinflammation in Alzheimer’s disease mice by controlling astrocyte activation. Cell Death & Diseaae 15: 858, 2024.
  3. Watanabe S, Amporndanai K, Awais R, Latham C, Awais M, O'Neill PM, Yamanaka K, Hasnain S: Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement. Scientific Reports 14, 12118, 2024.
  4. Wang T, Sobue A, Watanabe S, Komine O, Saido TC, Saito T, Yamanaka K: Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer’s disease. Journal of Neuroinflammation 21(1), 55, 2024.
  5. Komine O, Ohnuma S, Hinohara K, Hara Y, Shimada M, Akashi T, Watanabe S, Sobue A, Kawade N, Ogi T, Yamanaka K: Genetic background variation impacts microglial heterogeneity and disease progression in amyotrophic lateral sclerosis model mice. iScience 27(2), 108872, 2024.
2023
  1. Watanabe S, Murata Y, Oka Y, Oiwa K, Horiuchi M, Iguchi Y, Komine O, Sobue A, Katsuno M, Ogi T, Yamanaka K: Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS. Proceedings of the National Academy of Sciences of the United States of America 120(47): e2315347120, 2023.
  2. Oiwa K, Watanabe S, Onodera K, Iguchi Y, Kinoshita Y, KOmine O, Sobue A, Okada Y, Katsuno M, Yamanaka K: Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis. Science Advances 9(31): eadf6895, 2023.
  3. Kawade N, Yamanaka K: Novel insights into brain lipid metabolism in Alzheimer's disease: Oligodendrocytes and white matter abnormalities. FEBS Open Bio 14(2): 194-216, 2023.
  4. Hashimoto K, Watanabe S, Akutu M, Mukai N, Kamishina H, Furukawa Y, Yamanaka K: Intrinsic structural vulnerability in the hydrophobic core induces species-specific aggregation of canine SOD1 with degenerative myelopathy–linked E40K mutation. Journal of Biological Chemistry 299(6): 104798, 2023.
  5. Sobue A, Komine O, Yamanaka K: Neuroinflammation in Alzheimer’s disease: microglial signature and their relevance to disease. Inflammation & Regeneration 43: 26, 2023.
  6. Maekawa K, Yamanaka K: Role of sex hormones in neuroinflammation in Alzheimer's disease. Clinical & Experimental Neuroimmunology 4: 16 1045647, 2023.
  7. Watanabe S, Horiuchi M, Murata Y, Komine O, Kawade N, Sobue A, Yamanaka K: Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis. Neurobiology of Disease 2: 179 106031, 2023.
2022
  1. Yamashita H, Komine O, Fujimori-Tonou, N, Yamanaka K: Comprehensive expression analysis with cell-type-specific transcriptome in ALS-linked mutant SOD1 mice: Revisiting the active role of glial cells in disease. Frontiers in Cellular Neuroscience 4: 16 1045647, 2022.
2021
  1. Sakai S, Watanabe S, Komine O, Sobue A, and Yamanaka K: Novel reporters of mitochondria-associated membranes (MAM), MAMtrackers, demonstrate MAM disruption as a common pathological feature in amyotrophic lateral sclerosis. FASEB Journal e21688, 2021.
  2. Sobue A, Komine O, Hara Y, Endo F, Mizoguchi H, Watanabe S, Murayama S, Saito T, Saido T, Sahara N, Higuchi M, Ogi T and Yamanaka K: Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease. Acta Neuropathologica Communications 9: 1, 2021.
2020
  1. Watanabe S, Inami H, Oiwa K, Murata Y, Sakai S, Komine O, Sobue A, Iguchi Y, Katsuno M, Yamanaka K: Aggresome formation and liquid–liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43. Cell Death & Disease 11: 909, 2020.
  2. Amporndanai K, Rogers M, Watanabe S, Yamanaka K, O’Neill P. M., Hasnain S. S.: Novel Selenium-based compounds with therapeutic potential for SOD1-linked Amyotrophic Lateral Sclerosis. EBioMedicine 59: 102980, 2020.
  3. Watanabe S, Oiwa K, Murata Y, Komine O, Sobue A, Endo F, Takahashi E and Yamanaka K: ALS-linked TDP-43M337V knock-in mice exhibit splicing deregulation without neurodegeneration. Molecular Brain 13: 8, 2020.
2019
  1. Nishino K, Watanabe S, Shijie J, Murata Y, Oiwa K, Komine O, Endo F, Tsuiji H, Abe M, Sakimura K, Mishra A, Yamanaka K: Mice deficient in the C-terminal domain of TAR DNA-binding protein 43 develop age-dependent motor dysfunction associated with impaired Notch1-Akt signaling pathway. Acta Neuropathologica Communications 7(1): 118, 2019.
  2. Trias E, Barbeito L, Yamanaka K: Phenotypic heterogeneity of astrocytes in motor neuron disease. Clinical Experimantal Neurology 9(4): 225-234, 2018.
2018
  1. Komine O, Yamashita H, Fujimori-Tonou N, Koike M, Jin S, Moriwaki Y, Endo F, Watanabe S, Uematsu S, Akira S, Uchiyama Y, Takahashi R, Misawa H, Yamanaka K: Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes. Cell Death & Differentiation 25: 2130-2146, 2018.
2017
  1. Watanabe S, Komine O, Fumito E, Wakasugi K, Yamanaka K: Intracerebroventricular administration of Cystatin C ameliorates disease in SOD1-linked amyotrophic lateral sclerosis mice. Journal of Neurochemistry 145(1): 80-89, 2017.
  2. Yamanaka K, Komine O: The multi-dimensional roles of astrocytes in ALS. Neuroscience Research 126: 31-38, 2018.
  3. Tsuiji H, Inoue I, Takeuchi M, Furuya A, Yamakage Y, Watanabe S, Koike M, Hattori M, Yamanaka K: TDP-43 accelerates age-dependent degeneration of interneurons. Scientific Reports 7: 14972, 2017.
2016
  1. Endo F, Komine O, Yamanaka K: Neuroinflammation in motor neuron disease. Clinical and Experimental Neuroimmunology 7: 126-138, 2016.
  2. 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 Molecular Medicine 8(12): 1421-1437, 2016.
  3. 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 Neuropathologica Communications 4: 15, 2016
  4. 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. Neurobiology of Disease 86: 16, 2015.
2015
  1. Komine O & Yamanaka K: Neuroinflammation in motor neuron disease. Nagoya Journal of Medical Science 77: 537, 2015.
  2. Endo F & Yamanaka K: Astrocytic TGF-β1: detrimental factor in ALS. Oncogene 6: 15728, 2015.
  3. 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-β1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells. Cell Reports 11: 592, 2015.
  4. 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 Neurology 14: 388, 2015.
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 & Disease, 5: e1497, 2014.
  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 7: 62, 2014.
  3. 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. Proceedings of the Natural Academy of Sciences, USA 111: 4309-4314, 2014.
  4. 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. The Journal of Biological Chemistry, 289: 1192-1202, 2014.
2013
  1. Furukawa Y, Kaneko K, Watanabe S, Yamanaka K, Nukina N: Intracellular seeded aggregation of mutant Cu,Zn-superoxide dismutase associated with amyotrophic lateral sclerosis. FEBS Letters 587: 2500-2505, 2013.
  2. Iguchi Y, Katsuno M, Niwa J, 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, 136: 1371-1382, 2013.
  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. The Journal of Biological Chemistry, 288: 4970-4980, 2013.
  4. 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 Molecular Medicine, 5: 221-234, 2013.
  5. Watanabe S, Kaneko K, Yamanaka K: Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked TDP-43 mutations. The Journal of Biological Chemistry, 288: 3641-3654, 2013.
2012
  1. 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. Neurobiology of Aging, 34: 1310.e11-23, 2012.
2011
  1. Lasiene J, Yamanaka K: Glial cells in Amyotrophic Lateral Sclerosis. Neurology Research International 2011: 718987, 2011.
2008
  1. 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 Natural Academy of Sciences, USA, 105: 7594-7599, 2008.
  2. 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, 11: 251-253, 2008.
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, 312: 1389-1392, 2006.

MESSAGE

Our laboratory is currently recruiting graduate students for both the Master’s and PhD programs. In addition, undergraduate students, research students, and others are welcome to participate in our research in various capacities. If you are interested in our research, please feel free to contact us to mnd◎riem.nagoya-u.ac.jp for more details.(Please send a message after replacing "◎" mark with "@" mark. )

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