2022 Fiscal Year Final Research Report

A novel model of multiple sclerosis and multiple system atrophy that are differentially manifested by the time of abnormal protein expression

Research Project

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Project/Area Number	20K20470
Project/Area Number (Other)	19H05562 (2019)
Research Category	Grant-in-Aid for Challenging Research (Pioneering)
Allocation Type	Multi-year Fund (2020) Single-year Grants (2019)
Review Section	Medium-sized Section 52:General internal medicine and related fields
Research Institution	International University of Health and Welfare (2020-2022) Kyushu University (2019)
Principal Investigator	Kira Jun-ichi 国際医療福祉大学, 医学研究科, 教授 (40183305)
Co-Investigator(Kenkyū-buntansha)	立川正憲徳島大学, 大学院医歯薬学研究部(薬学域), 教授 (00401810) 松下拓也九州大学, 大学病院, 講師 (00533001) 山口浩雄九州大学, 大学病院, 特任講師 (00701830) 松瀬大九州大学, 医学研究院, 助教 (70596395)
Project Period (FY)	2019-06-28 – 2023-03-31
Keywords	神経変性疾患 / 脱髄疾患 / 多系統萎縮症 / 多発性硬化症 / αーシヌクレイン / ミクログリア / アストログリア / 小脳失調
Outline of Final Research Achievements	We developed a novel multiple system atrophy (MSA) model by oligodendrocyte-specific over-expression of human A53T mutant α-synuclein in adult mice using Tet-Off regulation. Transgenic mice presented rapidly progressive ataxia and prominent demyelination in the brainstem/cerebellum with phosphorylated α-synuclein accumulation and substantial glial activation. With late re-inhibition of α-synuclein production, clinicopathological deterioration persisted despite the resolution of aggregated α-synuclein. Single-cell RNA sequencing of brain CD11b+ cells revealed a unique microglia cluster highly expressing Tlr2, Tgm2, Arg1, Msr1, and inflammatory cytokine genes that surrounded phosphorylated α-synuclein aggregates. Prophylactic administration of a colony-stimulating factor 1 receptor inhibitor increased these α-synuclein-associated microglia and worsened demyelination. Thus, a unique α-synuclein-associated microglia subset engages in progressive demyelination and neurodegeneration.
Free Research Field	神経内科学
Academic Significance and Societal Importance of the Research Achievements	多系統萎縮症(MSA)は、小脳/錐体外路/自律神経等を侵す治療法のない神経変性疾患である。一方、多発性硬化症(MS)は代表的な中枢神経脱髄疾患である。MSとMSAで共通性のあるα-synの関与に着目し、凝集性の強い変異α-synA53TをTet-off系で任意の期間オリゴデンドログリアに発現できるマウスを樹立し、世界初のMSA-C（多系統萎縮症小脳型）モデルマウスを確立した。このマウスの解析により病原性の高いα-synucleinopathy-associated microglia (SAM)の同定に成功した。このモデルは、グリア炎症を標的とした新薬の開発に大きく貢献できる。