With the aging of the population, there is a tendency of the morbidity of neurodegenerative disorder. Parkinson’s Disease (PD), the second most common neurodegenerative disorder, is characterized by bradykinesia, rigidity, tremor, and loss of dopaminergic neurons. Familial mutations that cause PD have been identified, including the genes that encode alpha-synuclein and leucine-rich repeat kinase2 (LRRK2), which cause autosomal-dominant PD, as well as DJ-1, PINK1, and parkin, which cause autosomal-recessive PD.

However, the majority of PD cases are sporadic. The cause of sporadic PD and the role of environmental toxins and genetic factors in sporadic PD is unclear. The neurotoxins induce the formation of reactive oxygen species (ROS). Although oxidative stress plays a critical role in causing PD, the mechanisms underlying oxidative stress-induced PD remain unclear.

Prof. YUAN Zengqiang's laboratory from Institute of Biophysics (IBP) of Chinese Academy of Sciences has been dedicated to studying the molecular mechanisms regulating neuronal cell death in neurodegenerative diseases. In the previous studies, they found that Mst1/2 (Xiao et al., JNS, 2011) and FOXO family protein (Xie et al., EMBO Report, 2012 and Peng et al., JNS, 2015) play an important role in regulating neuronal death. A study from Prof. YUAN Zengqiang’s laboratory revealed the mechanism for dopaminergic neuronal death. The work entitled "c-Abl–p38α Signaling Plays an Important Role in MPTP-Induced Neuronal Death" is published in Cell Death & Differentiation.

In this study, the researchers demonstrated that non-receptor tyrosine kinase c-Abl is activated in oxidative stress-induced PD. Conditional knockout (KO) of c-Abl in neurons protects against MPTP-induced loss of dopaminergic neurons. Treatment with the c-Abl inhibitor STI571 also protects against MPTP-induced dopaminergic neurons death and ameliorates the locomotive defects induced by MPTP.

Using the stable isotope labeling with amino acids in cell culture (SILAC) technique and other biochemical methods, they showed that p38α is a novel c-Abl substrate that mediates oxidative stress-induced PD. C-Abl directly interacts with p38α and phosphorlates p38αat Y182 and Y323 site. P38α phosphorylation at Y323 by c-Abl promotes p38α homodimerization and activates p38α via a non-canonical pathway. The researchers believe that c-Abl phosphorylates p38α and promotes neuronal cell death in vivo. The inhibition of p38α using SB203580 mitigates the MPTP-induced loss of dopaminergic neurons and also ameliorates the locomotive defects induced by MPTP.

This study identified p38α as novel substrate of c-Abl during the MPTP-induced death of dopaminergic neurons. It provides further support for the crucial role of c-Abl in the development of PD. It would be valuable to explore the efficacy of c-Abl-p38α inhibition as a therapeutic strategy for PD in the future.

The work was supported by the National Science Foundation of China, the National Basic Research Program of China and Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation from Chinese Academy of Sciences.