Glucocorticoid Regulates Parkin Expression in Mouse Frontal Cortex: Implications in Schizophrenia

Abstract

Stress and glucocorticoid hormones, which are released into the circulation following stressful experiences, have been shown to contribute significantly to the manifestation of various psychiatric illnesses including schizophrenia and depression. Studies in rodents have reported dose and time dependent effects of glucocorticoids on the expression of proteins related to neuroplasticity. However, the mechanism(s) involved in the regulation of proteins by glucocorticoids are not clear. Ubiquitin ligases play important role in degradation, trafficking and stabilization of proteins. The present study investigated the effect of glucocorticoid on ubiquitin-proteasome system in mouse frontal cortex. A significant increase in mRNA and protein levels of parkin, an E3 ubiquitin ligase was found in cultured mouse primary cortical neurons following corticosterone treatment. An increase in parkin levels was also found in mouse frontal cortex in vivo following acute dexamethasone treatment. However, chronic treatment with corticosterone did not change parkin protein levels in mouse frontal cortex. Studies using postmortem brain samples from schizophrenia and control subjects indicated a significant increase in parkin protein levels in frontal cortex of schizophrenia subjects suggesting a response to increased stress conditions in schizophrenia. These findings suggest a possible role of parkin in the pathophysiology of stress-related psychiatric disorders.

Gene-wide Association Study Reveals RNF122 Ubiquitin Ligase as a Novel Susceptibility Gene for Attention Deficit Hyperactivity Disorder

“…The overexpression of RNF122 that we found in persistent ADHD is in agreement with previous studies reporting increased expression levels of E3 ubiquitin ligases in neuropsychiatric disorders 51 , 54 . Given its role in synaptic surface-protein turnover and in the regulation of the number of scaffolding proteins and neurotransmitter receptors, increased ubiquitin ligation and subsequent enhanced protein removal may compromise neuronal functioning 43 , 55 , 56 .…”

Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases?

“…While the definitive experiment has yet to be conducted, this finding suggests that a stress-induced increase in GC levels would result in an upregulation of parkin expression and accelerate abnormal protein accumulation in PD. That hypothesis is supported by a recent report that mouse cortical neurons in primary culture upregulate parkin mRNA and protein levels following corticosterone treatment ( 343 ).…”

Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson’s disease model

“…It has been reported that hydrocortisone can suppress ER stress 25 and the ATF4 signaling pathway in muscle tissues 26 . Hydrocortisone’s neuroprotective role by acting directly on neuronal cells has not been reported before, although there is a report showing that parkin induction in the frontal cortex by hydrocortisone might be implicated in Schizophrenia disorder 27 . Other parkin inducers including deferasirox, vorinostat, metformin, and clindamycin also elevated ER stress to some extent, consistent with previous reports on these compounds 28 – 30 .…”