Unraveling dual dysfunction in Friedreich’s ataxia: how mitochondrial dysfunction and microglial activation drive neurodegeneration

Abstract

Friedreich’s ataxia (FRDA) is hereditary recessive disorder that impacts muscular function at several levels. Currently 1 in 40,000 people are impacted by FRDA globally. FRDA is defined by multiple symptoms including progressive ataxia, dysarthria, sensory loss, cardiomyopathy, diabetes mellitus, and scoliosis. The typical onset occurs in early childhood or adolescence. Given the severity of the symptoms and the prevalence of FRDA it is important to understand the mechanism. This neurodegenerative disorder is caused by mutations in the FXN gene which leads to reduced expression of frataxin. It has been speculated that mitochondrial function could be contributing to FRDA. Frataxin is a mitochondrial protein crucial for iron-sulfur cluster biogenesis and mitochondrial function. When frataxin levels are depleted, mitochondrial dysfunction, increased oxidative stress, and impaired energy production are impacted which are central to understanding this disease. In order to determine if mitochondrial transplantation could be a viable treatment, we must first determine if we can identify a healthy mitochondria network within each cell. This study aims to elucidate the underlying mechanism of FRDA, with a key emphasis on mitochondrial network as well as the interplay between mitochondrial dysfunction and microglial activation. By identifying these dysfunctions, this research aims to provide an in-depth understanding of disease and provide insights into novel therapeutic approaches.