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

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.

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.

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.

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.