Single‐cell atlas of neuroglial dynamics in SNCA ‐ A53T Parkinson's disease mouse model

Background Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of midbrain substantia nigra dopaminergic neurons, resulting in striatal dopamine depletion and motor dysfunction. While this pathological cascade is well‐established, its underlying mechanisms remain elusive. Methods To further investigate the pathological mechanisms of PD, we performed single‐cell RNA sequencing of the midbrain and striatum from Hua‐Syn (SNCA*A53T) transgenic (A53T) mice as a PD model. Results Analysis of 22 865 midbrain and 32 117 striatal cells revealed cell‐type‐specific risk association. Glial populations (astrocytes, microglia, oligodendrocytes) showed significant enrichment for PD‐risk genes. Variance‐based clustering identified PD‐enriched subclusters exhibiting upregulated inflammatory pathways, apoptotic pathways, proteostasis disruption, glutamatergic signaling dysregulation, and mitochondrial respiratory chain defects. Transcriptional regulation analysis identified genes associated with PD specific activity, including Rorb and Foxc1 in the midbrain and Dbx2 and Klf13 in the striatum. Cell–cell interactions showed that cell‐to‐cell signaling was enhanced, and the SEMA and CCL neuroinflammatory axes were specifically activated in the PD group. Conclusions Our integrative analysis delineates the cellular and molecular architecture of the pathological process triggered by the expression of A53T mutant α‐synuclein, and provides a framework for targeted therapeutic development.