Investigating the action of genes and compounds that modify mitophagy and pro-survival pathways in cellular models of Parkinson’s disease

Abstract

Parkinson's disease (PD) is a neurodegenerative condition characterised by a loss of dopaminergic nigrostriatal nerve cells. Emerging evidence shows ageing, altered mitochondrial function, genetic factors and exposure to environmental toxins targeting mitochondria are major risk factors for idiopathic Parkinson’s disease. Dopaminergic neurons have uniquely complex dendritic networks and are therefore vulnerable to disruptions in energy homeostasis caused by mitochondrial dysfunction. Therefore, identifying drugs that improve mitochondrial function could be used to treat or prevent PD. This study focused on investigating whether GSK3α/β and CDK inhibitors improved mitochondrial function and neuronal health and had the potential to treat PD. Kenpaullone, a GSK3α/β and CDK inhibitor, was previously reported to improve the mitochondrial network and was shown to protect mitochondria following a PD-stressor (MPP+). This evidence suggested that studying drugs that target GSK3α/β and CDKs may give an insight into the mechanism governing mitochondrial quality control pathways and may lead to the discovery of drugs useful in treating Parkinson's disease. This study investigated drugs with similar targets to kenpaullone, namely AZD5438, AT7519, alsterpaullone and 1-azakenapaullone and mitochondrial protective drugs, dexpramipexole and olesoxime, that target mitochondria in a similar manner to kenpaullone. The findings showed that AZD5438, a potent GSK3α/β and CDK inhibitor, restores mitochondrial membrane potential and inhibits Parkin recruitment and fragmentation of the mitochondrial network following treatment with CCCP. Furthermore, AZD5438 was shown to improve mitochondrial networks and prevent the death of neurons (derived from human iPSC) following the treatment with the mitochondrial complex I inhibitor, rotenone. AZD5438 was also shown to inhibit mitochondrial ROS and neuronal apoptosis while it upregulated glycolysis and improved the electrophysiological function of neurons. Based on these novel findings, AZD5438 is suggested to have potential as a therapeutic drug for neurodegenerative diseases such as Parkinson's disease.

Date of Award	3 Nov 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	James B Uney (Supervisor)