Spatiotemporal profiling of white matter lesions and their contribution in the pathologies of Parkinson's disease animal models.

Increasing evidence has identified significant white matter lesions (WMLs) in Parkinson's disease (PD) patients. However, the complex relationships between WMLs and the neuropathological changes of PD remain unclear. In this study, we comprehensively elucidated the spatiotemporal dynamics of WMLs in rotenone-, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models, and α-synuclein (α-Syn) (A53T) transgenic mice. The results showed that WMLs occurred across multiple brain regions and gradually aggravated as PD models progressed. Notably, WMLs emerged as early pathological events of PD prior to dopaminergic neuronal loss. Consistently, WMLs-related axial movement disorders, including gait and balance impairments, preceded those caused by nigrostriatal injury. Further in vitro studies revealed that oligodendrocyte precursor cells (OPCs) dysfunction caused by 1-methyl-4-phenylpyridinium (MPP⁺) or α-Syn could induce dopaminergic axonal breakage and neuronal damage, confirming myelination disorder promoted dopaminergic neuronal degeneration. This finding was certified in additional in vivo studies using lysophosphatidylcholine (LPC)-induced demyelination models. The results validated that WMLs could independently induce dopaminergic neuronal damage and nigrostriatal pathway-related movement disorders. Moreover, comorbid WMLs in PD mice further aggravated this process. In summary, our findings uncovered the spatiotemporal characteristics of WMLs and their contribution to PD pathological development, highlighting that targeting WMLs might be a potential strategy for PD intervention.