STRIATAL CELL TYPE TRANSCRIPTOMIC REMODELING IN A PARKINSONIAN MOUSE MODEL

Single-cell transcriptomics provides a powerful approach to dissect the cellular heterogeneity of the brain, uncovering cell type-specific molecular alterations associated with neurodegenerative diseases such as Parkinson’s disease (PD). A critical hallmark of PD is the degeneration of the dopaminergic (DA) nigrostriatal pathway, which begins in the striatum (ST) and later affects the DA neurons of the SNc. The ST plays a central role in motor control and is particularly vulnerable in early PD; however, the molecular responses of its neuronal and glial populations to DA denervation remain poorly characterized. In this study, we performed single-cell RNA sequencing to characterize transcriptional alterations across major striatal cell populations in the MCI-Park mouse model of PD. In this model, genetic deletion of mitochondrial complex I function selectively in DA neurons is sufficient to induce progressive, human-like parkinsonism, from a prodromic to a symptomatic stage. Cells were isolated from flash-dissected striata of prodromic and symptomatic MCI-Park mice and age-matched wild-type (WT) littermates. Our data reveal marked transcriptomic remodeling across multiple striatal cell classes. Several neuronal and glial subtypes were selectively enriched in older mice, including a distinct oligodendrocyte subtype exclusively detected in symptomatic MCI-Park mice. Notably, alterations in striatal cell composition were already evident at the prodromic MCI-Park stage, with Nalf1-expressing direct-pathway medium spiny neurons predominantly present in prodromic mice. Together, these findings provide a high-resolution, cell type-specific map of adaptive and pathological transcriptional changes in the ST following early nigrostriatal denervation, offering new insights into the molecular dynamics underlying early parkinsonian vulnerability.