α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson's disease

Retinal degeneration is prominent in Parkinson's disease (PD), a neuromotor disorder associated with aggregation of a-synuclein (alpha-syn) in the substantia-nigra (SN). Although alpha-syn is expressed in the neuroretina, absence of prominent aggregates suggests altered function as the likely cause of retinal pathology. We demonstrate that alpha-syn impairs ferritinophagy, resulting in the accumulation of iron-rich ferritin in the outer retina in-vivo and retinal-pigment-epithelial (RPE) cells in-vitro. Over-expression of Rab1a restores ferritinophagy, suggesting that alpha-syn impairs lysosomal function by disrupting the trafficking of lysosomal hydrolases. Surprisingly, upregulation of ferritin in RPE cells by exogenous iron in-vitro stimulated the release of ferritin and alpha-syn in exosomes, suggesting that iron overload due to impaired ferritinophagy or other cause(s) is likely to initiate prion-like spread of alpha-syn and ferritin, creating retinal iron dyshomeostasis and associated cytotoxicity. Since over-expression of alpha-syn is a known cause of PD, these results explain the likely cause of PD-associated retinal degeneration.