Neurotoxicity, α-Synuclein Pathology, and Mitochondrial Dysfunction: A Comparative Study of Three Parkinson’s Disease Mouse Models

The pathogenesis of Parkinson’s disease (PD) is complex, and it is difficult for a single animal model to fully mimic its pathological features. In this study, a comprehensive analysis of behaviors, PD-like pathologies, and gene and protein expression profiles was carried out in PD mouse models (MPTP-induced, α-Syn A53T transgenic, and MitoPark models). The three PD models showed motor impairments, with MitoPark mice displaying particularly pronounced age-related worsening. Pathologically, they all exhibited nigrostriatal pathway damage but showed differential patterns of glial cell activation. All three PD model mice showed no α-Syn aggregates. However, a few pS129-α-Syn-positive signals were detected in the substantia nigra of α-Syn A53T transgenic mice. Molecularly, RNA sequencing and proteomics revealed significant changes in gene and protein expression, with both unique and common features. Five common differentially expressed genes (Ifi27l2a, Ifitm3, Oasl2, Rtp4, and Ankk1) and two common differentially expressed proteins (Timm8a1 and Sephs1) were identified. Functional enrichment analysis indicated that immune responses, cytokines, and neurotransmitter transport were crucial in PD pathogenesis. Pathway analysis revealed the involvement of ferroptosis in all models, with additional IL-17 pathway activation specifically in MitoPark mice. These findings provide a comprehensive molecular and phenotypic characterization of PD models, offering valuable insights into disease mechanisms and potential therapeutic targets.