Unravelling mitochondrial impairment in spinocerebellar ataxia 3: insights from neuroblastoma cells and human induced pluripotent stem cells

Abstract

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by the abnormal CAG repeat expansion in the ATXN3 gene, resulting in an expanded polyglutamine tract within the ataxin-3 protein. Despite significant progress in comprehending SCA3 etiology, the underlying disease mechanisms remain elusive, lacking effective treatments. This study employed two in vitro models to explore the impact of pathogenic SCA3 on ER stress and mitochondrial function: (1) human neuroblastoma SH-SY5Y cells expressing normal (28 CAG repeats) and pathogenic (84 CAG repeats) ataxin-3; (2) dopaminergic neurons derived from SCA3 patient-induced pluripotent stem cells (iPSCs) and an isogenic control. Our observations from these SCA3 cell models unveiled that expanded ataxin-3 triggers endoplasmic reticulum stress, activating PERK and IRE1 pathways in SCA3 patient-derived DA neurons, alongside inducing mitochondrial dysfunction, leading to decreased oxygen consumption and impaired mitochondrial respiration. This pioneering study harnessed SCA3-specific cellular targets, such as dopaminergic neurons and SH-SY5Y cells stably expressing ataxin-3, yielding valuable insights into SCA3 pathogenesis pathways, highlighting the potential roles of ER stress and mitochondrial dysfunction. These findings might catalyze the development of novel treatments aimed at mitigating the effects of expanded ataxin-3 and restoring cellular health.