Akt Phosphorylates NQO1 and Triggers its Degradation, Abolishing Its Antioxidative Activities in Parkinson's Disease

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.

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

“…Studies have shown that AKT also plays a role in PD signal transduction. As serine/threonine-specific protein kinases, AKT and phosphorylated AKT are significantly reduced in the substantia nigra pars compacta (SNpc) of PD patients [92]. PI3K/AKT/mTOR pathway activation also promotes the survival and growth of dopamine neurons by inhibiting apoptosis, thus preventing PD [93].…”

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

“…Oxidative phosphorylation is a vital part of metabolism, takes place in the mitochondria, and contributes to the major source of ATP. This process also leads to the generation of reactive oxygen species (ROS) and resulting oxidative stress and bioenergetics defects, which are linked to a range of neurodegenerative disorders, including PD [37][38][39]. While oxidative stress has been shown to play significant roles both in the onset and progression of PD [40], it still remains open to debate whether the mitochondrial respiratory deficiencies observed in a range of neurodegenerative disorders are initiators or consequences of prior insult [41].…”

A Dynamic Core in Human NQO1 Controls the Functional and Stability Effects of Ligand Binding and Their Communication across the Enzyme Dimer

“…The Pro187Ser variant decreases NQO1 activity due to a large defect in FAD binding (10- to 40-fold lower affinity than that of WT) and in conformational stability, leading to its rapid intracellular degradation by the proteasome [1,10,14,16,22,23,24,25]. In general, reduced NQO1 activity or protein levels are commonly observed under these pathological conditions [1,26], although for the particular case of cancer, overexpression of NQO1 is also associated with cancer progression, which makes pharmacological inhibition of NQO1 (e.g., by dicoumarol or related compounds) a potential therapeutic strategy to treat this disease if it selectively targets cancer cells [27,28,29]. Linked to some of these pathological conditions, the intracellular stability of NQO1 WT is controlled by the population of the NQO1 apo state, which is efficiently targeted to the ubiquitin-dependent proteasomal degradation pathway [14,25,30].…”