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

被引:43
作者
Baksi, Shounak [1 ]
Singh, Neena [1 ]
机构
[1] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA
基金
美国国家卫生研究院;
关键词
AUTOPHAGY; NEURODEGENERATION; PHAGOCYTOSIS; DEGRADATION; HOMEOSTASIS; RELEVANCE; RECEPTOR; EXOSOMES; BRAIN; NCOA4;
D O I
10.1038/s41598-017-12862-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:14
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