Akt phosphorylates NQO1 and triggers its degradation, abolishing its antioxidative activities in Parkinson’s disease

Shilin Luo, Seong Su Kang, Zhi Hao Wang, Xia Liu, Julia X. Day, Zhiping Wu, Junmin Peng, Daxiong Xiang, Wolfdieter Springer, Keqiang Ye

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The oxidative metabolism of dopamine and consequent oxidative stress are implicated in dopaminergic neuronal loss, mediating the pathogenesis of Parkinson’s disease (PD). The inducible detoxifying antioxidative enzyme Quinone oxidoreductase (NQO1) (NAD(P)H: quinone oxidoreductase 1), neuroprotective to counteract reactive oxidative species, is most prominent in the active stage of the disease and virtually absent at the end stage of the disease. However, the molecular mechanism dictating NQO1 expression oscillation remains unclear. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase. Unphosphorylatable NQO1 mutant displays more robust neuroprotective activity than WT NQO1 in suppressing reactive oxidative species and against MPTP-induced dopaminergic cell death, rescuing the motor disorders in both ⍺-synuclein transgenic transgenic male and female mice elicited by the neurotoxin. Thus, our findings demonstrate that blockade of Akt-mediated NQO1 degradation may ameliorate PD pathogenesis.

Original languageEnglish (US)
Pages (from-to)7291-7305
Number of pages15
JournalJournal of Neuroscience
Volume39
Issue number37
DOIs
StatePublished - 2019

Keywords

  • Akt
  • Antioxidative activity
  • NQO1
  • Parkinson’s disease
  • Phosphorylation
  • Ubiquitination

ASJC Scopus subject areas

  • Neuroscience(all)

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