Parkin knockout inhibits neuronal development via regulation of proteasomal degradation of p21

PARK2 encodes for the E3 ubiquitin ligase parkin and iimplicates in the development of Parkinsons disease (PD). Although the neuroprotective role of parkin is well known, the mechanism of parkins function in neural stem differentiation is not clear. Co-expressions network analysis showed that SNAP25 and BDNF were positively correlated with parkin, but negatively correlated with p21 in human patient brain. Therefore, we investigated a link between the ubiquitin E3 ligase parkin and proteasomal degradation of p21 for the control of neural stem cell differentiation. We discovered that p21 directly binds with parkin and is ubiquitinated by parkin resulting in the loss of cell differentiation ability. Tranfection of p21 shRNA in PARK2 KO mice significantly rescued the differentiation efficacy as well as SNAP25 and BDNF expression. We also defined the decreased p21 ubiquitination and differentiation ability were reversed after treatment with JNK inhibitor, SP600125 in PARK2 KO mice derived neural stem cells. Thus, the present study indicated that parkin knockout inhibits neural stem cell differentiation by JNK-dependent proteasomal degradation of p21.\n\nSummary statementThe present study indicated that parkin knockout inhibits neural stem cell differentiation by JNK-dependent proteasomal degradation of p21.