Midnolin is a novel regulator of parkin expression and is associated with Parkinson's Disease

Abstract

Midnolin (MIDN) was first discovered in embryonic stem cells, but its physiological and pathological roles are, to date, poorly understood. In the present study, we therefore examined the role of MIDN in detail. We found that in PC12 cells, a model of neuronal cells, MIDN localized primarily to the nucleus and intracellular membranes. Nerve growth factor promoted MIDN gene expression, which was attenuated by specific inhibitors of extracellular signal-regulated kinases 1/2 and 5. MIDN-deficient PC12 cells created using CRISPR/Cas9 technology displayed significantly impaired neurite outgrowth. Interestingly, a genetic approach revealed that 10.5% of patients with sporadic Parkinson's disease (PD) had a lower MIDN gene copy number whereas no copy number variation was observed in healthy people, suggesting that MIDN is involved in PD pathogenesis. Furthermore, the expression of parkin, a major causative gene in PD, was significantly reduced by CRISPR/Cas9 knockout and siRNA knockdown of MIDN. Activating transcription factor 4 (ATF4) was also down-regulated, which binds to the cAMP response element (CRE) in the parkin core promoter region. The activity of CRE was reduced following MIDN loss. Overall, our data suggests that MIDN promotes the expression of parkin E3 ubiquitin ligase, and that MIDN loss can trigger PD-related pathogenic mechanisms.