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DJ ‐1 deficiency impairs autophagy and reduces alpha‐synuclein phagocytosis by microglia
Author(s) -
Nash Yuval,
Schmukler Eran,
Trudler Dorit,
PinkasKramarski Ronit,
Frenkel Dan
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14222
Subject(s) - microglia , autophagy , microbiology and biotechnology , neurotoxicity , proinflammatory cytokine , intracellular , phagocytosis , neurodegeneration , alpha synuclein , chemistry , biology , parkinson's disease , biochemistry , inflammation , immunology , medicine , apoptosis , disease , organic chemistry , toxicity
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 .