| RRC ID |
85993
|
| Author |
Harada M, Masaki K, Tanaka T, Sekiya H, Matsuse D, Yamaguchi H, Nishimura Y, Takase EO, Tanaka E, Kira YI, Fujishima K, Matsuo E, Yamasaki R, Dickson DW, Suzumura A, Taniwaki T, Hoshino T, Isobe N, Takeuchi H, Kira JI.
|
| Title |
Facilitated α-synuclein oligomer sharing among glial cells by a centrally acting connexin inhibitor attenuates a rapidly progressive multiple system atrophy-cerebellar type model by reducing the neuronal α-synuclein burden.
|
| Journal |
Acta Neuropathol Commun
|
| Abstract |
Glial connexins (Cxs) that make up astrocyte/oligodendrocyte gap junctions are extensively altered in multiple system atrophy-cerebellar type (MSA-C). Here, we investigated how Cx alterations affect the propagation of α-synuclein (α-syn) oligomers and phosphorylated (p)-α-syn aggregates in MSA-C using a centrally acting pan-Cx blocker, INI-0602. Our Plp1-tTA::tetO-SNCA*A53T transgenic (Tg) mice express mutant human A53T α-syn in oligodendrocytes after dietary doxycycline withdrawal at 8 weeks of age; they typically develop progressive ataxia around 22 weeks and die by 30 weeks. These Tg mice were intraperitoneally administered INI-0602 or vehicle from 18 to 26 weeks of age. Proximity ligation assay demonstrated that α-syn oligomers in small glial cells of the brainstem/cerebellum peaked at 10 weeks and maintained similar levels thereafter. In neuropil, α-syn oligomers appeared at 10 weeks, peaked at 16 weeks, and decreased from 24 weeks. In large cells (neuronal somata or reactive astrocytes), α-syn oligomers continuously accumulated from 10 to 30 weeks. By contrast, p-α-syn accumulated predominantly in oligodendrocytes from 24 to 30 weeks and later appeared in astrocytes, microglia, and neurons. Notably, double staining revealed that α-syn oligomers and p-α-syn were rarely colocalised. In the lesion centre with abundant p-α-syn deposits, both oligodendrocytic Cx47/Cx32 and astrocytic Cx43/Cx30 expression were extensively lost. Conversely, at the leading edges, Cx43 was upregulated despite Cx47 loss, resulting in abundant Cx43 hemichannels. INI-0602 suppressed increased hemichannel activity in the leading edges in acute slice culture and attenuated MSA-C and glial inflammation-thereby preserving Cx gap junctions-in Tg mice. INI-0602 treatment reduced neuronal α-syn oligomers and p-α-syn aggregates but facilitated α-syn oligomer dissemination throughout glial cells and neuropil. In human MSA-C, distinct distribution patterns between α-syn oligomers and p-α-syn deposits were also observed. Thus, increased sharing of α-syn oligomers via preserved Cx gap junctions may help attenuate MSA-C pathology by reducing neuronal α-syn aggregates.
|
| Volume |
13(1)
|
| Pages |
197
|
| Published |
2025-9-24
|
| DOI |
10.1186/s40478-025-02116-7
|
| PII |
10.1186/s40478-025-02116-7
|
| PMID |
40993788
|
| PMC |
PMC12462231
|
| MeSH |
Animals
Cerebellum / drug effects
Cerebellum / metabolism
Cerebellum / pathology
Connexins* / antagonists & inhibitors
Connexins* / metabolism
Disease Models, Animal
Gap Junctions / drug effects
Gap Junctions / metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Multiple System Atrophy* / drug therapy
Multiple System Atrophy* / metabolism
Multiple System Atrophy* / pathology
Neuroglia* / drug effects
Neuroglia* / metabolism
Neuroglia* / pathology
Neurons* / drug effects
Neurons* / metabolism
Neurons* / pathology
Oligodendroglia / drug effects
Oligodendroglia / metabolism
alpha-Synuclein* / genetics
alpha-Synuclein* / metabolism
|
| IF |
5.883
|
| Resource |
| Mice |
RBRC05446 |
