Retinal Pathology and Synucleinopathy in the Visual Pathway of α-Synuclein Preformed Fibril Mouse Model of Parkinson's Disease.

Abstract

BACKGROUND: Visual dysfunction is a common nonmotor manifestation of Parkinson's disease (PD) that may precede motor symptoms. This study aimed to characterize the early preformed fibril (PFF) mouse model of PD. METHODS: Male C57BL/6J mice received intrastriatal injections of α-synuclein (α-syn) PFFs or phosphate-buffered saline. Visual function was evaluated at 3 and 6 months postinjection using pattern visual evoked potentials (PVEPs) and the visual cliff test. Retinal morphology and protein expression were assessed by hematoxylin-eosin staining, immunofluorescence, and Western blot analysis for phosphorylated α-syn (pS129), tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and Iba1. Pathological α-syn distribution in the visual pathway and association cortices was examined by fluorescence microscopy. RESULTS: At 3 months, PFF-injected mice showed prolonged PVEP latency and reduced amplitude, indicating early visual pathway dysfunction, which worsened by 6 months. Retinal structure was preserved, but p-α-syn accumulation appeared in ganglion cells, accompanied by reduced TH expression and activation of microglia and Müller glia. The pSer129-immunoreactive structures were detected in the visual cortex and visual association cortices, including frontal, parietal, temporal, and amygdaloid regions. CONCLUSIONS: Functional and pathological alterations in the visual system emerge before motor deficits in α-syn PFF-injected mice. Early retinal and cortical synucleinopathy may underlie prodromal visual dysfunction and serve as potential biomarkers for early PD diagnosis.