Research Institute of Environmental Medicine Nagoya University

The molecular mechanism of neurodegenerative diseases such as motor neuron disease (amyotrophic lateral sclerosis, ALS) remains 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 ALS patients in future.

1. Wang T, Sobue A, Watanabe S, Komine O, Saido TC, Saito T, and Yamanaka K. Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer's disease. Journal of Neuroinflammation 21(1), 55, 2024.
2. Komine O, Ohnuma S, Hinohara K, Hara Y, Shimada M, Akashi T, Watanabe S, Sobue A, Kawade N, Ogi T, and Yamanaka K. Genetic background variation impacts microglial heterogeneity and disease progression in amyotrophic lateral sclerosis model mice. iScience 27(2), 108872, 2024.
3. Watanabe S, Murata Y, Oka Y, Horiuchi M, Iguchi Y, Komine O, Sobue A, Okada Y, Katsuno M, Ogi T, and 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.
4. Oiwa K, Watanabe S, Onodera K, Iguchi Y, Kinoshita Y, Komine O, Sobue A, Okada Y, Katsuno M, and 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.
5. Hashimoto K, Watanabe S, Akutu M, Mukai N, Kamishina H, Furukawa Y, and 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.
6. Watanabe S, Horiuchi M, Murata Y, Komine O, Kawade N, Sobue A, and 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.
7. 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. The FASEB Journal e21688, 2021.
8. 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.
9. 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 & Disease11: 909, 2020.
10. 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.
11. Nishino K, Watanabe S, Jin S, 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.
12. 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 Mololecular Medicine 8(12): 1421-1437, 2016.
13. Endo F, Komine O, Fujimori-Tonou N, Jin S, Watanabe S, Katsuno M, 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 Reports 11: 592, 2015.
14. 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.
15. Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, KassiotisG, KolliasG, Cleveland DW. Onset and Progression in Inherited ALS determined by Motor Neurons and Microglia. Science 312: 1389-1392, 2006.

(May 2, 2018)