Objective: We aimed to develop a rapidly progressive mouse model that recapitulates MSA-C pathology.

Background: Multiple system atrophy (MSA) is a severe α-synucleinopathy driven by glial activation, with the cerebellar variant (MSA-C) primarily affecting olivopontocerebellar fibers and exhibiting significant demyelination. The absence of robust models targeting olivopontocerebellar tracts in adulthood has limited our understanding of demyelination and neuroaxonal loss, hindering the development of effective treatments for MSA. To address this, a reliable MSA-C model is crucial for understanding disease mechanisms and developing therapies.

Method: We generated Plp1-tTA::tetO-SNCAA53T bi-transgenic mice by crossing Plp1-tTA mice with tetO-SNCAA53T mice. In these mice, human A53T α-synuclein, a mutant protein with enhanced aggregability, was specifically produced in oligodendrocytes of adult mice from 8 weeks of age using Tet-Off regulation. We performed motor function and histological evaluations of these mice. We also conducted experiments to inhibit human A53T α-synuclein expression after the onset of neurological symptoms.

Results: Bi-transgenic mice developed ataxic gait by 22 weeks and died around 30 weeks, exhibiting severe brainstem and cerebellar demyelination. Microglial and astrocytic activation was evident, with increased inflammatory markers and cytokine production. α-synuclein oligomers first appeared in oligodendrocytes at 9 weeks, later spreading to astrocytes, neuropil, and neurons at 12–16 weeks. Phosphorylated α-synuclein progressively increased, closely associating with demyelination and oligodendrocytic loss. Inhibition of human A53Tα-synuclein at 23 weeks reversed demyelination, while suppression at 27 weeks failed to restore myelin integrity. These results highlight the importance of early intervention in preventing neurodegeneration.

Conclusion: Our bi-transgenic MSA-C model exhibits progressive demyelination, neuroaxonal loss, and severe motor dysfunction, closely mimicking human MSA-C pathology. This model of MSA is useful for elucidating the in vivo mechanisms of α-synuclein spreading from glia to neurons, and for developing therapies that target glial reactions and/or α-synuclein oligomer spreading and aggregate formation in MSA.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-rapidly-progressive-multiple-system-atrophy-cerebellar-variant-model-presenting%ce%b1-synuclein-oligomer-spreading-and-phosphorylated-%ce%b1-synuclein-aggregate-formation-accompanied-with-glial-infl/