Akt Phosphorylates NQ01 and Triggers its Degradation, Abolishing Its Antioxidative Activities in Parkinson's Disease

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 (NQ01) (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 NQ01 expression oscillation remains unclear. Here we show that Akt phosphorylates NQ01 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQ01 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQ01 phosphorylation and polyubiquitination with Parkin as an E3 ligase. Unphosphorylatable NQ01 mutant displays more robust neuroprotective activity than WT NQ01 in suppressing reactive oxidative species and against MPTP-induced dopaminergic cell death, rescuing the motor disorders in both alpha-synuclein transgenic transgenic male and female mice elicited by the neurotox in. Thus, our findings demonstrate that blockade of Akt-mediated NQ01 degradation may ameliorate PD pathogenesis.