Nonreceptor Tyrosine Kinase c-Abl-Mediated PHB2 Phosphorylation Aggravates Mitophagy Disorder in Parkinson’s Disease Model

Abstract

Mitophagy and oxidative stress play important roles in Parkinson’s disease (PD). Dysregulated mitophagy exacerbates mitochondrial oxidative damage; however, the regulatory mechanism of mitophagy is unclear. Here, we provide a potential mechanistic link between c-Abl, a nonreceptor tyrosine kinase, and mitophagy in PD progression. We found that c-Abl activation reduces the interaction of prohibitin 2 (PHB2) and microtubule-associated protein 1 light chain 3 (LC3) and decreases the expressive level of antioxidative stress proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2), NADPH quinone oxidoreductase-1 (NQO-1), and the antioxidant enzyme heme oxygenase-1 (HO-1) in 1-methyl-4-phenylpyridinium- (MPP+-) lesioned SH-SY5Y cells. Importantly, we found that MPP+ can increase the expression of phosphorylated proteins at the tyrosine site of PHB2 and the interaction of c-Abl with PHB2. We showed for the first time that PHB2 by changing tyrosine (Y) to aspartate (D) at site 121 resulted in impaired binding of PHB2 and LC3 in vitro. Moreover, silencing of PHB2 can decrease the interaction of PHB2 and LC3 and exacerbate the loss of dopaminergic neurons. We also found that STI 571, a c-Abl family kinase inhibitor, can decrease dopaminergic neuron damage and ameliorate MPTP-induced behavioral deficits in PD mice. Taken together, our findings highlight a novel molecular mechanism for aberrant PHB2 phosphorylation as an inhibitor of c-Abl activity and suggest that c-Abl and PHB2 are potential therapeutic targets for the treatment of individuals with PD. However, these results need to be further validated in PHB2 Y121D mice.

PHB2 Alleviates Neurotoxicity of Prion Peptide PrP106–126 via PINK1/Parkin-Dependent Mitophagy

“…Several studies have demonstrated the protective role of PHB2-mediated mitophagy in various diseases. One study reported that the depletion of PHB2 decreased the interaction between PHB2 and LC3, resulting in reduced mitophagy and exacerbated loss of dopaminergic neurons in a Parkinson's disease mouse model [64]. Lai and co-workers reported that Rutin, a natural botanical ingredient, attenuated oxidative damage, through PHB2-mediated mitophagy, in MPP + -treated SH-SY5Y cells [65].…”

Pgam5-mediated PHB2 dephosphorylation contributes to endotoxemia-induced myocardial dysfunction by inhibiting mitophagy and the mitochondrial unfolded protein response

“…Previous studies have reported that Pgam5 induces PHB2 dephosphorylation in the setting of diabetic cardiomyopathy [35]. Since Pgam5 ablation is able to protect the heart against inflammation-related injury, we asked whether Pgam5 contributes to endotoxin-related cardiomyocyte dysfunction by dephosphorylating PHB2.…”

“…Recent studies have found that several phosphorylation reactions on PHB2 residues determine its intracellular sub-localization [35,36]. Thus, dephosphorylated PHB2 is primarily detected in the cytoplasm, whereas phosphorylated PHB2 localizes in the mitochondria [36][37][38].…”

Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases

“…PLG exerted its beneficial effects by preventing apoptosis and inducing autophagy, which was mediated by enhanced phosphorylation of BCL2 at Ser70 [ 45 ]. These results that c-Abl and PHB2 may serve as potential therapeutic targets for the treatment of PD [ 46 ]. Using imaging mass cytometry to analyze postmortem human brain sections from patients with PD, Chun Chen et al found that astrocytes, like neurons, are vulnerable to mitochondrial defects, which could affect their reactivity and ability to support neurons in PD [ 47 ].…”