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.

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

SUBMITTER: Harada M 

PROVIDER: S-EPMC12462231 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature