The USP13-SKP2-P57/kip2 Axis Mediates Spautin-1-Induced Transcriptional Upregulation of NURR1: Potential implications in the differentiation of dopamine neurons

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Abstract The progressive loss of midbrain dopamine neurons leading to motor deficits is the primary cause of Parkinson’s disease (PD). Emerging reports on the role of NURR1 in the differentiation and maintenance of dopamine neurons; the association of reduced levels / familial mutants of NURR1 in PD subjects makes it a promising candidate for developing disease-modifying therapy. In the present study, while examining the effects of known deubiquitinase inhibitors, we have identified that the USP10/13 inhibitor, spautin-1, upregulated NURR1 levels in a transcription-dependent manner. Further, USP13, but not USP10, was found to be essential in spautin-1-mediated NURR1 regulation. Reports indicate that USP13 deubiquitinates SKP2 and thereby prevents it from degradation. Also, SKP2 is an E3 ligase for P57/kip2 and reduced SKP2 expression leads to enhanced P57/kip2 levels. In line with the above findings, cells treated with spautin-1 exhibited reduced SKP2 with a concomitant increase in P57/kip2 levels. Our results indicate that spautin-1-mediated regulation of the USP13-SKP2-P57/kip2 axis plays a crucial role in NURR1 upregulation since overexpression of SKP2, or knockdown of P57/kip2, abrogated spautin-1-mediated effects. Further, spautin-1 mediated neurite outgrowth of dopaminergic cells was mitigated under NURR1 knockdown condition, indicating that small molecule activators of NURR1 could promote dopaminergic cell differentiation. Lastly, the ability of spautin-1 in enhancing tyrosine hydroxylase staining in vivo in the PD mouse model suggests that pharmacological activation of NURR1 could serve as a promising strategy for the disease-modifying effects of PD.

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