論文 - 森﨑　祐太

Type selective ablation of postnatal slow and fast fatigue-resistant motor neurons in mice induces late onset kinetic and postural tremor following fiber-type transition and myopathy

Misawa H., Kamishima K., Koyama T., Ohgaki L., Morisaki Y., Yamanaka T., Itohara S., Sawano S., Mizunoya W., Ogihara N.

Experimental Neurology （Experimental Neurology）  376 2024年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00144886

　概要を見る

Animals on Earth need to hold postures and execute a series of movements under gravity and atmospheric pressure. VAChT-Cre is a transgenic Cre driver mouse line that expresses Cre recombinase selectively in motor neurons of S-type (slow-twitch fatigue-resistant) and FR-type (fast-twitch fatigue-resistant). Sequential motor unit recruitment is a fundamental principle for fine and smooth locomotion; smaller-diameter motor neurons (S-type, FR-type) first contract low-intensity oxidative type I and type IIa muscle fibers, and thereafter larger-diameter motor neurons (FInt-type, FF-type) are recruited to contract high-intensity glycolytic type IIx and type IIb muscle fibers. To selectively eliminate S- and FR-type motor neurons, VAChT-Cre mice were crossbred with NSE-DTA mice in which the cytotoxic diphtheria toxin A fragment (DTA) was expressed in Cre-expressing neurons. The VAChT-Cre;NSE-DTA mice were born normally but progressively manifested various characteristics, including body weight loss, kyphosis, kinetic and postural tremor, and muscular atrophy. The progressive kinetic and postural tremor was remarkable from around 20 weeks of age and aggravated. Muscular atrophy was apparent in slow muscles, but not in fast muscles. The increase in motor unit number estimation was detected by electromyography, reflecting compensatory re-innervation by remaining FInt- and FF-type motor neurons to the orphaned slow muscle fibers. The muscle fibers gradually manifested fast/slow hybrid phenotypes, and the remaining FInt-and FF-type motor neurons gradually disappeared. These results suggest selective ablation of S- and FR-type motor neurons induces progressive muscle fiber-type transition, exhaustion of remaining FInt- and FF-type motor neurons, and late-onset kinetic and postural tremor in mice.

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LAG-3 expression in microglia regulated by IFN-γ/STAT1 pathway and metalloproteases

Morisaki Y., Ohshima M., Suzuki H., Misawa H.

Frontiers in Cellular Neuroscience （Frontiers in Cellular Neuroscience）  17 2023年11月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り,  ISSN  16625102

　概要を見る

Microglia are resident innate immune cells in the central nervous system (CNS) and play important roles in the development of CNS homeostasis. Excessive activation and neurotoxicity of microglia are observed in several CNS disorders, but the mechanisms regulating their activation remain unclear. Immune checkpoint molecules are expressed on activated immune cells and regulate their activation in peripheral immunity. However, the expression mechanism of immune checkpoint molecules in activated microglia is still unknown. Here, we analyzed the expression of immune checkpoint molecules in activated microglia using the mouse microglial cell line BV2 and primary cultured microglia. The expression of lymphocyte activation gene-3 (LAG-3), a type of immune checkpoint molecule, was increased in microglia activated by IFN-γ. IFN-γ-induced LAG-3 expression in microglia was suppressed by transfection of siRNA targeting STAT1. LAG-3 has two forms, membrane and soluble, and both forms were upregulated in microglia activated by IFN-γ. The production of soluble LAG-3 was suppressed by treatment with inhibitors of metalloproteinases such as ADAM10 and ADAM17. IFN-γ administration into cisterna magna of mice increased LAG-3 expression in spinal microglia. Furthermore, LAG-3 knockdown in microglia promoted nitric oxide production by IFN-γ. Our results demonstrate that LAG-3 expression in microglia is induced by the IFN-γ-STAT1 pathway and soluble LAG-3 production is regulated via cleavage of membranous LAG-3 by metalloproteinases including ADAM10 and ADAM17.

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Depletion of perivascular macrophages delays ALS disease progression by ameliorating blood-spinal cord barrier impairment in SOD1-G93A mice

Kazuki Adachi, Kota Miyata, Yukino Chida, Mikako Hirose, Yuta Morisaki, Koji Yamanaka, Hidemi Misawa

Frontiers in Cellular Neuroscience 2023年11月

研究論文（学術雑誌）, 共著, 査読有り

A copper-deficient form of mutant Cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis

Tokuda Eiichi, Nomura Takao, Ohara Shinji, Watanabe Seiji, Yamanaka Koji, Morisaki Yuta, Misawa Hidemi, Furukawa Yoshiaki

Biochimica et Biophysica Acta - Molecular Basis of Disease 2018年06月

研究論文（学術雑誌）, 共著, 査読有り

Immunochemical characterization on pathological oligomers of mutant Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis

Tokuda Eiichi, Anzai Itsuki, Nomura Takao, Toichi Keisuke, Watanabe Masahiko, Ohara Shinji, Watanabe Seiji, Yamanaka Koji, Morisaki Yuta, Misawa Hidemi, Furukawa Yoshiaki

Molecular Neurodegeneration 2017年01月

研究論文（学術雑誌）, 共著, 査読有り

Selective expression of osteopontin in ALS-resistant motor neurons is a critical determinant of late phase neurodegeneration mediated by matrix metalloproteinase-9

Morisaki Yuta, Niikura Mamiko, Watanabe Mizuho, Onishi Kosuke, Tanabe Shogo, Moriwaki Yasuhiro, Okuda Takashi, Ohara Shinji, Murayama Shigeo, Takao Masaki, Uchida Sae, Yamanaka Koji, Misawa Hidemi

Scientific Reports 2016年06月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り