Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages

Abstract To examine the pathogenic role of α-synuclein (αS) in Parkinson’s Disease, we have generated induced Pluripotent Stem Cell lines from early onset Parkinson’s Disease patients with SNCA A53T and SNCA Triplication mutations, and in this study have differentiated them to PSC-macrophages (pMac)...

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Autores principales:	Walther Haenseler, Federico Zambon, Heyne Lee, Jane Vowles, Federica Rinaldi, Galbha Duggal, Henry Houlden, Katrina Gwinn, Selina Wray, Kelvin C. Luk, Richard Wade-Martins, William S. James, Sally A. Cowley
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/079e9c373cb245c5abd9ca8f629f34fc
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spelling	oai:doaj.org-article:079e9c373cb245c5abd9ca8f629f34fc2021-12-02T15:05:16ZExcess α-synuclein compromises phagocytosis in iPSC-derived macrophages10.1038/s41598-017-09362-32045-2322https://doaj.org/article/079e9c373cb245c5abd9ca8f629f34fc2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09362-3https://doaj.org/toc/2045-2322Abstract To examine the pathogenic role of α-synuclein (αS) in Parkinson’s Disease, we have generated induced Pluripotent Stem Cell lines from early onset Parkinson’s Disease patients with SNCA A53T and SNCA Triplication mutations, and in this study have differentiated them to PSC-macrophages (pMac), which recapitulate many features of their brain-resident cousins, microglia. We show that SNCA Triplication pMac, but not A53T pMac, have significantly increased intracellular αS versus controls and release significantly more αS to the medium. SNCA Triplication pMac, but not A53T pMac, show significantly reduced phagocytosis capability and this can be phenocopied by adding monomeric αS to the cell culture medium of control pMac. Fibrillar αS is taken up by pMac by actin-rearrangement-dependent pathways, and monomeric αS by actin-independent pathways. Finally, pMac degrade αS and this can be arrested by blocking lysosomal and proteasomal pathways. Together, these results show that macrophages are capable of clearing αS, but that high levels of exogenous or endogenous αS compromise this ability, likely a vicious cycle scenario faced by microglia in Parkinson’s disease.Walther HaenselerFederico ZambonHeyne LeeJane VowlesFederica RinaldiGalbha DuggalHenry HouldenKatrina GwinnSelina WrayKelvin C. LukRichard Wade-MartinsWilliam S. JamesSally A. CowleyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Walther Haenseler Federico Zambon Heyne Lee Jane Vowles Federica Rinaldi Galbha Duggal Henry Houlden Katrina Gwinn Selina Wray Kelvin C. Luk Richard Wade-Martins William S. James Sally A. Cowley Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages
description	Abstract To examine the pathogenic role of α-synuclein (αS) in Parkinson’s Disease, we have generated induced Pluripotent Stem Cell lines from early onset Parkinson’s Disease patients with SNCA A53T and SNCA Triplication mutations, and in this study have differentiated them to PSC-macrophages (pMac), which recapitulate many features of their brain-resident cousins, microglia. We show that SNCA Triplication pMac, but not A53T pMac, have significantly increased intracellular αS versus controls and release significantly more αS to the medium. SNCA Triplication pMac, but not A53T pMac, show significantly reduced phagocytosis capability and this can be phenocopied by adding monomeric αS to the cell culture medium of control pMac. Fibrillar αS is taken up by pMac by actin-rearrangement-dependent pathways, and monomeric αS by actin-independent pathways. Finally, pMac degrade αS and this can be arrested by blocking lysosomal and proteasomal pathways. Together, these results show that macrophages are capable of clearing αS, but that high levels of exogenous or endogenous αS compromise this ability, likely a vicious cycle scenario faced by microglia in Parkinson’s disease.
format	article
author	Walther Haenseler Federico Zambon Heyne Lee Jane Vowles Federica Rinaldi Galbha Duggal Henry Houlden Katrina Gwinn Selina Wray Kelvin C. Luk Richard Wade-Martins William S. James Sally A. Cowley
author_facet	Walther Haenseler Federico Zambon Heyne Lee Jane Vowles Federica Rinaldi Galbha Duggal Henry Houlden Katrina Gwinn Selina Wray Kelvin C. Luk Richard Wade-Martins William S. James Sally A. Cowley
author_sort	Walther Haenseler
title	Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages
title_short	Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages
title_full	Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages
title_fullStr	Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages
title_full_unstemmed	Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages
title_sort	excess α-synuclein compromises phagocytosis in ipsc-derived macrophages
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/079e9c373cb245c5abd9ca8f629f34fc
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Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages

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