Retina-to-brain spreading of [alpha]-synuclein after intravitreal injection of preformed fibrils

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of misfolded [alpha]-synuclein and progressive spreading of the aggregates from a few discrete regions to wider brain regions. Although PD has been classically considered a movement disorder, a large body of clinical evidence has revealed the progressive occurrence of non-motor symptoms. Patients present visual symptoms in the initial stages of the disease, and accumulation of phospho-[alpha]-synuclein, dopaminergic neuronal loss, and retinal thinning has been observed in the retinas of PD patients. Based on such human data, we hypothesized that [alpha]-synuclein aggregation can initiate in the retina and spread to the brain through the visual pathway. Here, we demonstrate accumulation of [alpha]-synuclein in the retinas and brains of naive mice after intravitreal injection of [alpha]-synuclein preformed fibrils (PFFs). Histological analyses showed deposition of phospho-[alpha]-synuclein inclusions within the retina 2 months after injection, with increased oxidative stress leading to loss of retinal ganglion cells and dopaminergic dysfunction. In addition, we found accumulation of phospho-[alpha]-synuclein in cortical areas with accompanying neuroinflammation after 5 months. Collectively, our findings suggest that retinal synucleinopathy lesions initiated by intravitreal injection of [alpha]-synuclein PFFs spread to various brain regions through the visual pathway in mice. Keywords: Parkinson's disease, [alpha]-synuclein, Protein aggregation, Retina, Retinal degeneration