α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson's disease.
α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson's disease.
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DOI：
10.1038/s41598-017-12862-x
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发表时间：
2017-10-09
影响因子：
4.6
通讯作者：
Singh N
中科院分区：
文献类型：
--
作者：
Baksi S;Singh N
视网膜变性在帕金森病(PD)中尤为突出，帕金森病是一种与黑质(SN)α-突触核蛋白(α-SYN)聚集相关的神经运动障碍。虽然α-SYN在神经视网膜中表达，但没有明显的聚集体表明功能改变是视网膜病理的可能原因。我们证明α-SYN可以抑制吞铁蛋白，导致富含铁的铁蛋白在体内视网膜外层细胞和体外培养的视网膜色素上皮细胞中积累。过表达的Rab1a恢复了铁蛋白吞噬功能，表明α-syn通过破坏溶酶体水解酶的运输而损害溶酶体的功能。令人惊讶的是，外源性铁在体外上调了视网膜色素上皮细胞中铁蛋白的表达，刺激了外体中铁蛋白和α-syn的释放，这表明由于铁蛋白吞噬功能受损或其他原因导致的铁超载很可能启动α-syn和铁蛋白的普恩样扩散，造成视网膜铁代谢紊乱和相关的细胞毒性。由于α-SYN的过度表达是PD的已知原因，这些结果解释了PD相关性视网膜变性的可能原因。
Retinal degeneration is prominent in Parkinson’s disease (PD), a neuromotor disorder associated with aggregation of α-synuclein (α-syn) in the substantia-nigra (SN). Although α-syn is expressed in the neuroretina, absence of prominent aggregates suggests altered function as the likely cause of retinal pathology. We demonstrate that α-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 α-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 α-syn in exosomes, suggesting that iron overload due to impaired ferritinophagy or other cause(s) is likely to initiate prion-like spread of α-syn and ferritin, creating retinal iron dyshomeostasis and associated cytotoxicity. Since over-expression of α-syn is a known cause of PD, these results explain the likely cause of PD-associated retinal degeneration.
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DOI：
10.1111/j.1600-0854.2008.00853.x
发表时间：
2009-02
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Ben Gedalya T;Loeb V;Israeli E;Altschuler Y;Selkoe DJ;Sharon R
通讯作者：
Sharon R
DOI：
10.4061/2011/908306
发表时间：
2011
期刊：
Parkinson's disease
影响因子：
--
作者：
Armstrong RA
通讯作者：
Armstrong RA
影响因子：
7.4
作者：
Baksi S;Tripathi AK;Singh N
通讯作者：
Singh N
影响因子：
4.1
作者：
Archibald, N. K.;Clarke, M. P.;Burn, D. J.
通讯作者：
Burn, D. J.
影响因子：
5.4
作者：
Klein, Christine;Westenberger, Ana
通讯作者：
Westenberger, Ana