Tnfaip8 l1/Oxi‐β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model

Abstract

Abnormal autophagy may contribute to neurodegeneration in Parkinson's disease (PD). However, it is largely unknown how autophagy is dysregulated by oxidative stress (OS), one of major pathogenic causes of PD. We recently discovered the potential autophagy regulator gene family including Tnfaip8/Oxi-α, which is a mammalian target of rapamycin (mTOR) activator down-regulated by OS in dopaminergic neurons (J. Neurochem., 112, 2010, 366). Here, we demonstrate that the OS-induced Tnfaip8l1/Oxi-β could increase autophagy by a unique mechanism that increases the stability of tuberous sclerosis complex 2 (TSC2), a critical negative regulator of mTOR. Tnfaip8l1/Oxi-β and Tnfaip8/Oxi-α are the novel regulators of mTOR acting in opposition in dopaminergic (DA) neurons. Specifically, 6-hydroxydopamine (6-OHDA) treatment up-regulated Tnfaip8l1/Oxi-β in DA neurons, thus inducing autophagy, while knockdown of Tnfaip8l1/Oxi-β prevented significantly activation of autophagic markers by 6-OHDA. FBXW5 was identified as a novel binding protein for Tnfaip8l1/Oxi-β. FBXW5 is a TSC2 binding receptor within CUL4 E3 ligase complex, and it promotes proteasomal degradation of TSC2. Thus, Tnfaip8l1/Oxi-β competes with TSC2 to bind FBXW5, increasing TSC2 stability by preventing its ubiquitination. Our data show that the OS-induced Tnfaip8l1/Oxi-β stabilizes TSC2 protein, decreases mTOR phosphorylation, and enhances autophagy. Therefore, altered regulation of Tnfaip8l1/Oxi-β may contribute significantly to dysregulated autophagy observed in dopaminergic neurons under pathogenic OS condition. Dysfunctional autophagy is frequently observed in post-mortem brains of patients and animal models of Parkinson's disease. In dopaminergic neurons of the 6-hydroxydopamine (6-OHDA) model, oxidative stress induces Tnfaip8l1/Oxi-β, which results in increased autophagy by its exclusive binding with FBXW5 to stabilize TSC2. Thus, altered regulation of Tnfaip8l1/Oxi-β may contribute to dysregulated autophagy in dopaminergic neurons under pathogenic oxidative stress, implicating both Oxi-β and FBXW5 as potential intervention targets for dysfunctional autophagy in dopaminergic neurons under oxidative stress.