Temporal progression of pathological features in an α-synuclein overexpression model of Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disorder, affecting 1–5% of individuals over 60, with a higher incidence in men. It is clinically characterized by progressive motor impairments, including rigidity, bradykinesia, tremors, and gait disturbances. The neuropathological hallmark of PD is the aggregation of α-synuclein (α-syn) into Lewy bodies (LB) and neurites (LN). Although α-syn plays essential physiological roles, its misfolding and accumulation drive neurodegeneration. In this study, we investigated the temporal progression and anatomical distribution of α-syn pathology using a bilateral adeno-associated virus serotype-9 (AAV9)-mediated α-syn overexpression model in rats. Disease-related features were analyzed at one, two and four months post-injection. Neuronal α-syn overexpression was confirmed as it co-localized predominantly with tyrosine hydroxylase (TH)-positive neurons, distinctly separate from glial markers. Behavioral assessment, immunofluorescence assays, stereological quantification, and optical densitometry revealed progressive motor impairments, dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), and decreased TH + fibers in the striatum and dendrites of the substantia nigra pars reticulata (SNpr). These changes were accompanied by increased microglial activation. Furthermore, axonal swellings in the striatum increased progressively over time, correlating with reductions in striatal TH optical density. By characterizing the temporal dynamics of α-syn-induced pathology, this study underscores the model’s relevance for PD research and highlights critical time windows for evaluating therapeutic interventions.