Extensive disruption of connexin gap junction in multiple system atrophy

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20873
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Kyushu University
• Principal Investigator: Hayashida Shotaro 九州大学, 医学研究院, 共同研究員 (60907385)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: 多系統萎縮症 / コネキシン / ギャップ結合 / グリア細胞

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.

Free Research Field

神経病理学

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。