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ABSTRACT Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by alpha-(α)-Synuclein neuronal aggregation and loss of dopaminergic (DA) neurons. Developing animal models that replicate PD’s neuropathological phenotypes is critical for understanding its pathophysiology and evaluating potential therapeutic targets. In this study, we show that direct unilateral injection of human α-Synuclein PFFs into the Substantia Nigra (SN) of mutant A53T α-synuclein overexpressing mice induce bilateral phosphorylated α-Synuclein (pS129) pathology in the SN. This pathology spreads to the striatum, cerebral cortex, and midbrain within 60 days and is accompanied by neuroinflammation in the midbrain and cerebral cortex. Additionally, we observed synuclein-dependent neurodegeneration, with a 50% reduction in Tyrosine Hydroxylase (TH) intensity in the SN and a 40% reduction in Striatum, both bilaterally. The model also revealed a compromised blood-brain barrier (BBB) and T-cell infiltration in the PFF injected animals, correlating with pS129 pathology and neuroinflammation. Taken together, we developed a mouse model that recapitulates multiple PD phenotypes, providing a valuable platform for testing therapeutic strategies targeting human α-Synuclein pathology and for exploring CNS-peripheral immune interactions in PD. Graphical Abstract
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