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Sci Rep. 2017 Aug 21;7(1):9003. doi: 10.1038/s41598-017-09362-3.

Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages.

Author information

1
James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK. hwalther@gmx.ch.
2
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK.
3
Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX3 9DS, UK.
4
James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
5
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DS, UK.
6
Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
7
National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
8
Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
9
James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK. sally.cowley@path.ox.ac.uk.
10
Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX3 9DS, UK. sally.cowley@path.ox.ac.uk.

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.

PMID:
28827786
PMCID:
PMC5567139
DOI:
10.1038/s41598-017-09362-3
[Indexed for MEDLINE]
Free PMC Article

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