Temporal Progression of Pathological Features in an α-Synuclein Overexpression Model of Parkinson's Disease

Parkinson's disease (PD) is a prevalent neurodegenerative disorder affecting 1-5% of individuals over 60, with a higher incidence in men. It is characterized by progressive motor impairments, such as 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). While α-syn plays essential physiological roles, its misfolding and accumulation drive neurodegeneration. This study investigates the temporal progression and distribution of α-syn pathology using adeno-associated viral (AAV9) vectors-mediated α-syn overexpression model in rats, analyzing disease features at one, two and four months post-injection. We first confirmed the neuronal specificity of α-syn overexpression, as it co-localized exclusively with tyrosine hydroxylase (TH)-positive neurons, distinctly separate from glial markers. Then, through behavioral assessment, immunofluorescence, stereological quantification, and optical densitometry, we observed progressive motor impairments, dopaminergic cell loss in the substantia nigra pars compacta (SNpc), and a reduction in TH+ fibers in both the striatum and the substantia nigra pars reticulata (SNpr), accompanied by increased microglial activation. Additionally, axonal swellings in the striatum progressively increased, correlating with reductions in striatal optical density. By delineating the time-dependent progression of α-syn-induced pathology, this study reinforces the model’s relevance for PD research and identifies critical time points for therapeutic interventions.