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

ABSTRACT: To examine the pathogenic role of ?-synuclein (?S) 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 ?S versus controls and release significantly more ?S to the medium. SNCA Triplication pMac, but not A53T pMac, show significantly reduced phagocytosis capability and this can be phenocopied by adding monomeric ?S to the cell culture medium of control pMac. Fibrillar ?S is taken up by pMac by actin-rearrangement-dependent pathways, and monomeric ?S by actin-independent pathways. Finally, pMac degrade ?S and this can be arrested by blocking lysosomal and proteasomal pathways. Together, these results show that macrophages are capable of clearing ?S, but that high levels of exogenous or endogenous ?S compromise this ability, likely a vicious cycle scenario faced by microglia in Parkinson's disease.

SUBMITTER: Haenseler W

PROVIDER: S-EPMC5567139 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Haenseler Walther W Zambon Federico F Lee Heyne H Vowles Jane J Rinaldi Federica F Duggal Galbha G Houlden Henry H Gwinn Katrina K Wray Selina S Luk Kelvin C KC Wade-Martins Richard R James William S WS Cowley Sally A SA

Scientific reports 20170821 1

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 ...[more]

PMID: 28827786

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Project description:α-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive, and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of α-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here, we expand this knowledge by investigating the effects of native, physiological α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called "cisternae." In addition, brain-derived α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of α-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.

Dataset Information

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

Publications

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

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