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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 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 retin...

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Autores principales: Baksi, Shounak, Singh, Neena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634503/
https://www.ncbi.nlm.nih.gov/pubmed/28993630
http://dx.doi.org/10.1038/s41598-017-12862-x
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author Baksi, Shounak
Singh, Neena
author_facet Baksi, Shounak
Singh, Neena
author_sort Baksi, Shounak
collection PubMed
description 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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spelling pubmed-56345032017-10-18 α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease Baksi, Shounak Singh, Neena Sci Rep Article 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. Nature Publishing Group UK 2017-10-09 /pmc/articles/PMC5634503/ /pubmed/28993630 http://dx.doi.org/10.1038/s41598-017-12862-x Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Baksi, Shounak
Singh, Neena
α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease
title α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease
title_full α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease
title_fullStr α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease
title_full_unstemmed α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease
title_short α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease
title_sort α-synuclein impairs ferritinophagy in the retinal pigment epithelium: implications for retinal iron dyshomeostasis in parkinson’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634503/
https://www.ncbi.nlm.nih.gov/pubmed/28993630
http://dx.doi.org/10.1038/s41598-017-12862-x
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