Identifying Therapeutic Agents for Amelioration of Mitochondrial Clearance Disorder in Neurons of Familial Parkinson Disease

Abstract

Summary Parkinson disease (PD) is a neurodegenerative disorder caused by the progressive loss of midbrain dopaminergic neurons, and mitochondrial dysfunction is involved in its pathogenesis. This study aimed to establish an imaging-based, semi-automatic, high-throughput system for the quantitative detection of disease-specific phenotypes in dopaminergic neurons from induced pluripotent stem cells (iPSCs) derived from patients with familial PD having Parkin or PINK1 mutations, which exhibit abnormal mitochondrial homeostasis. The proposed system recapitulates the deficiency of mitochondrial clearance, ROS accumulation, and increasing apoptosis in these familial PD-derived neurons. We screened 320 compounds for their ability to ameliorate multiple phenotypes and identified four candidate drugs. Some of these drugs improved the locomotion defects and reduced ATP production caused by PINK1 inactivation in Drosophila and were effective for idiopathic PD-derived neurons with impaired mitochondrial clearance. Our findings suggest that the proposed high-throughput system has potential for identifying effective drugs for familial and idiopathic PD.

Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

“…This is opposite to the mitochondrial morphology phenotype we have previously reported in PRKN mutant fibroblasts 5 ; however others in the literature have previously reported a more fragmented mitochondrial network associated with PRKN deficiency 45 ; this is likely to be a cell type specific effect; our data suggesting this is dependent on the metabolic status of the cells. As outlined in the introduction, several studies have found mitochondrial abnormalities in PRKN mutant patient derived neurons derived via iPSC reprogramming route [10][11][12][13][14][15][16][17] . Here we show some of the same abnormalities are present in PRKN mutant generated via a direct reprogramming route; in addition we have shown how this mitochondrial phenotype develops throughout differentiation and built upon previous studies in patient derived neurons to investigate multiple parameters related to neuronal health and mitochondria in the same population of neurons.…”

“…Recent work suggests mitophagy is defective across many PD types 9 . Several reports have found alterations in the same mitochondrial parameters in iPSC derived PRKN deficient neurons [10][11][12][13][14][15][16][17] . These studies provide insight into a mitochondrial phenotype in PRKN deficient neurons; several have identified mitochondrial functional and morphological abnormalities as well as increased cell death occurring in PRKN mutant neurons.…”

<p>Antioxidant, Anti-Inflammatory and Anti-Apoptotic Activities of Nesfatin-1: A Review</p>

“…39 Increasing evidence indicate that PD is related to mitochondrial dysfunction through multiple pathways, including free radical generation, inflammation, and apoptosis. 40,41 Numerous studies have shown that apoptosis, induced by mitochondrial dysfunction, plays a vital role in the incidence and development of PD, 42,43 suggesting that inhibition of apoptosis may be one of the treatment strategies for PD. Recently, rotenone-treated MES23.5 dopaminergic cells, a cellular model of PD, were used to study the neuroprotective effect of nesfatin-1 in PD and to understand the underlying mechanisms.…”

Targeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities

“…Another agent, celastrol, was shown to exert neuroprotective effects through activating mitophagy and inhibiting dopaminergic neuronal loss in PD cell and mouse models (Lin et al, 2019). Recently, a study used a high-throughput phenotype detection system for drug screening in dopaminergic neurons from induced-pluripotent stem cells (iPSCs) derived from patients with PD due to PRKN or PINK1 mutations (Yamaguchi et al, 2020). After screening 320 compounds, they identified 4 candidate drugs that were effective for ameliorating impaired mitochondrial clearance, showing the utility of this method for identifying candidate PD drugs (Yamaguchi et al, 2020).…”