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Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages

by Lee, Heyne , Vowles, Jane , Haenseler, Walther , Wray, Selina , Gwinn, Katrina , Wade-Martins, Richard , Duggal, Galbha , James, William S. , Houlden, Henry , Rinaldi, Federica , Cowley, Sally A. , Luk, Kelvin C. , Zambon, Federico

in 13/100 / 13/21 / 13/31 / 14 / 14/1 / 14/35 / 14/63 / 631/250/371 / 631/378/371 / Actin / Adult / Aged / Aged, 80 and over / alpha-Synuclein - genetics / alpha-Synuclein - metabolism / Brain research / Cell culture / Cell Differentiation / Cell lines / Cloning / Cytokines / Female / Flow cytometry / Gene Dosage / Gene expression / Humanities and Social Sciences / Humans / Macrophages / Macrophages - drug effects / Macrophages - immunology / Male / Microglia / Middle Aged / multidisciplinary / Mutation / Mutation, Missense / Parkinson Disease - pathology / Parkinson's disease / Pathology / Patients / Phagocytosis / Phagocytosis - drug effects / Pluripotency / Pluripotent Stem Cells / Proteasomes / Proteins / Science / Science (multidisciplinary) / Stem cells / Synuclein

2017

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Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages

2017

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Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages

2017

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Journal Article

Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages

Lee, Heyne,

Vowles, Jane,

Haenseler, Walther,

Wray, Selina,

Gwinn, Katrina,

Wade-Martins, Richard,

Duggal, Galbha,

James, William S.,

Houlden, Henry,

Rinaldi, Federica,

Cowley, Sally A.,

Luk, Kelvin C.,

Zambon, Federico

2017

Overview

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.

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Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio

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