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Increased O‐GlcNAcylation Attenuates Autophagic Flux, Induces Mitochondrial Dysfunction and Leads to Accumulation of Alpha‐Synuclein in Neurons
Author(s) -
Wani Willayat Yousuf,
Benavides Gloria,
Ahmad Israr,
Shacka John,
Chacko Balu,
Chatham John C,
Paterson Andrew J,
DarleyUsmar Victor M,
Zhang Jianhua
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.742.2
Subject(s) - autophagy , mitochondrion , alpha synuclein , bioenergetics , microbiology and biotechnology , parkinson's disease , chemistry , western blot , medicine , homeostasis , endocrinology , wild type , biology , biochemistry , apoptosis , disease , mutant , gene
Alpha‐synuclein accumulation and mitochondrial dysfunction are prominent in Parkinson's disease (PD). To determine how autophagy, the cellular protein homeostasis and mitochondrial quality control process is regulated by a nutrient sensing post‐translational modification pathway, the O‐linked attachment of β‐N‐acetyl‐glucosamine on protein S/T residues (O‐GlcNAcylation), we first performed western blot analyses of lysates from postmortem temporal cortex of controls and PD patients, and found significantly increased O‐GlcNAcylation levels in PD brains compared to control. Whether increased O‐GlcNAcylation affects neuronal function and survival was then tested in rat primary cortical neurons. We found that thiamet G, a highly selective inhibitor of the O‐GlcNAcase (OGA) that removes O‐GlcNAc modification, significantly increased protein O‐GlcNAcylation, decreased autophagic flux, decreased mitochondrial complex IV activities, increased accumulation of mitochondrial peroxynitrite, and led to an increased α‐synuclein accumulation. To confirm our results in vivo, we assessed cortical synaptosomal characteristics in wildtype and dnOGA transgenic (CaMKIIα‐tTA::Tet‐dnOGA, dominant negative OGA with a catalytic site deletion) mice. We found that dnOGA synaptosomes exhibited increased O‐GlcNAcylation, decreased mitochondrial function, increased α‐synuclein, and accumulation of autophagosomes. Taken together we proposed that a significant increase of O‐GlcNAcylation levels in PD brains may contribute to impairment of neuronal bioenergetics and attenuation of autophagic activities and accumulation of α‐synuclein. Support or Funding Information UAB School of Medicine Multi‐Investigator Pilot Grant and NIH R01‐NS064090 (JZ)