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DJ‐1 deficiency impairs autophagy and reduces alpha‐synuclein phagocytosis by microglia

Nash, Yuval, Schmukler, Eran, Trudler, Dorit, Pinkas‐Kramarski, Ronit, Frenkel, Dan·2017·Journal of Neurochemistry
DOI 10.1111/jnc.14222
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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder, of which 1% of the hereditary cases are linked to mutations in DJ‐1, an oxidative stress sensor. The pathological hallmark of PD is intercellular inclusions termed Lewy Bodies, composed mainly of α‐Synuclein (α‐Syn) protein. Recent findings have shown that α‐Syn can be transmitted from cell to cell, suggesting an important role of microglia, as the main scavenger cells of the brain, in clearing α‐Syn. We previously reported that the knock down (KD) of DJ‐1 in microglia increased cells’ neurotoxicity to dopaminergic neurons. Here, we discovered that α‐Syn significantly induced elevated secretion of the proinflammatory cytokines IL‐6 and IL‐1β and a significant dose‐dependent elevation in the production of nitric oxide in DJ‐1 KD microglia, compared to control microglia. We further investigated the ability of DJ‐1 KD microglia to uptake and degrade soluble α‐Syn, and discovered that DJ‐1 KD reduces cell‐surface lipid raft expression in microglia and impairs their ability to uptake soluble α‐Syn. Autophagy is an important mechanism for degradation of intracellular proteins and organelles. We discovered that DJ‐1 KD microglia exhibit an impaired autophagy‐dependent degradation of p62 and LC 3 proteins, and that manipulation of autophagy had less effect on α‐Syn uptake and clearance in DJ‐1 KD microglia, compared to control microglia. Further studies of the link between DJ‐1, α‐Syn uptake and autophagy may provide useful insights into the role of microglia in the etiology of the PD. image

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Metadata

Authors
Nash, Y., Schmukler, E., Trudler, D., Pinkas‐Kramarski, R., & Frenkel, D.
Affiliations
  • Sagol School of Neuroscience Tel Aviv University Tel Aviv Israel
  • Department of Neurobiology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2017-10-30
Volume
143
Issue
5
Pages
584-594
ISSN
  • 0022-3042
  • 1471-4159
DOI
10.1111/jnc.14222
Cited by
100
References
10
Language
en
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Funders
  • Slovak Academic Information Agency
  • Tel Aviv University

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