Extensive disruption of connexin gap junction in multiple system atrophy
| Project/Area Number |
21K20873
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0902:General internal medicine and related fields
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2021-08-30 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 多系統萎縮症 / コネキシン / ギャップ結合 / グリア細胞 / シヌクレイン / オリゴデンドロサイト / ミクログリア / マクロファージ |
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| Outline of Research at the Start |
多系統萎縮症（multiple system atrophy: MSA）の神経病理学的所見の中核とされるオリゴデンドロサイトにおけるα-synuclein（αSyn）蓄積とグリア細胞質封入体（glial cytoplasmic inclusion: GCI）形成が、どのような経路を介して脱髄や神経細胞死を引き起こすのか未解明な点が多い。私たちは、グリア細胞間情報伝達を担うコネキシン（Cx）蛋白群や、ミクログリア・アストロサイトを含むグリアネットワークに着目し、αSynと脳内恒常性グリアネットワーク破綻という全く新しい視点からMSAの病態解明と新規治療法開発を推進する。
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| Outline of Final Research Achievements |
The pathological hallmark of multiple system atrophy (MSA) is aberrant accumulation of phosphorylated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions (GCIs). Extensive demyelination occurs in the olivopontocerebellar and striatonigral pathways. Glial connexins (Cxs) play critical roles in myelin maintenance. We investigated glial Cx changes in 15 autopsied patients with MSA. We classified lesions into three stages: early (Stage I), intermediate (Stage II), and late (Stage III) stages. Accumulation of phosphorylated α-synuclein in oligodendrocytes was frequently seen in Stage I but less frequently observed in Stages II and III. Even at Stage I, Cx32 was absent from myelin. Cx32 was re-distributed in the oligodendrocyte cytoplasm and co-localized with GCIs. Astrocytic Cx43 was down-regulated in Stage I.Early and extensive alterations of glial Cxs occur in MSA and may accelerate demyelination.
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| Academic Significance and Societal Importance of the Research Achievements |
多系統萎縮症は原因不明で進行の速い難治性の神経変性疾患であり、病態解明や新規治療法開発が大きく期待されている。今回の研究成果は多系統萎縮症における脱髄や神経細胞脱落の病態を考える上で、ギャップ結合の破綻という全く新しい機序を提唱したものであり、実際に多系統萎縮症剖検例で検討したことも大きな成果である。今後はギャップ結合やコネキシンに着目した新規治療法開発を推進する。
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Report
(3 results)
Research Products
(3 results)
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[Journal Article] Early and extensive alterations of glial connexins, distal oligodendrogliopathy type demyelination, and nodal/paranodal pathology are characteristic of multiple system atrophy2022
Author(s)
Yuji Nishimura, Katsuhisa Masaki, Dai Matsuse, Hiroo Yamaguchi, Tatsunori Tanaka1, Eriko Matsuo, Shotaro Hayashida, Mitsuru Watanabe, Takuya Matsushita, Shoko Sadashima, Naokazu Sasagasako, Ryo Yamasaki, Noriko Isobe, Toru Iwaki, Jun-ichi Kira
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Journal Title
Brain Pathology
Volume: -
Issue: 3
Pages: 1-16
DOI
Related Report
Peer Reviewed / Open Access
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