Pharmacological rescue of mitochondrial and neuronal defects in SPG7 hereditary spastic paraplegia patient neurons using high throughput assays

Frontiers in Neuroscience

Neuroscience

Gautam Wali¹  Erandhi Liyanage²  Carolyn M. Sue²  Yan Li²  Margot L. Day³  Kishore R. Kumar⁴ 

[1] Neuroscience Research Australia, Sydney, NSW, Australia;Kolling Institute for Medical Research, University of Sydney, NSW, Australia;Neuroscience Research Australia, Sydney, NSW, Australia;Kolling Institute for Medical Research, University of Sydney, NSW, Australia;University of New South Wales, Sydney, NSW, Australia;School of Medical Science, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia;University of New South Wales, Sydney, NSW, Australia;Translational Neurogenomics Group, Molecular Medicine Laboratory and Department of Neurology, Concord Repatriation General Hospital, Concord Clinical School, University of Sydney, Concord, NSW, Australia;Garvan Institute of Medical Research, Darlinghurst, NSW, Australia;

关键词: hereditary spastic paraplegia (HSP);    mitochondria;    induced pluripotent stem (iPS) cell;    cortical neurons;    high throughput imaging (HTI);   

DOI  :  10.3389/fnins.2023.1231584

 received in 2023-05-30, accepted in 2023-08-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

SPG7 is the most common form of autosomal recessive hereditary spastic paraplegia (HSP). There is a lack of HSP-SPG7 human neuronal models to understand the disease mechanism and identify new drug treatments. We generated a human neuronal model of HSP-SPG7 using induced pluripotent stem (iPS) cell technology. We first generated iPS cells from three HSP-SPG7 patients carrying different disease-causing variants and three healthy controls. The iPS cells were differentiated to form neural progenitor cells (NPCs) and then from NPCs to mature cortical neurons. Mitochondrial and neuronal defects were measured using a high throughout imaging and analysis-based assay in live cells. Our results show that compared to control NPCs, patient NPCs had aberrant mitochondrial morphology with increased mitochondrial size and reduced membrane potential. Patient NPCs develop to form mature cortical neurons with amplified mitochondrial morphology and functional defects along with defects in neuron morphology − reduced neurite complexity and length, reduced synaptic gene, protein expression and activity, reduced viability and increased axonal degeneration. Treatment of patient neurons with Bz-423, a mitochondria permeability pore regulator, restored the mitochondrial and neurite morphological defects and mitochondrial membrane potential back to control neuron levels and rescued the low viability and increased degeneration in patient neurons. This study establishes a direct link between mitochondrial and neuronal defects in HSP-SPG7 patient neurons. We present a strategy for testing mitochondrial targeting drugs to rescue neuronal defects in HSP-SPG7 patient neurons.

【 授权许可】

Unknown   
Copyright © 2023 Wali, Li, Liyanage, Kumar, Day and Sue.