Unravelling cell type sensitivity to frataxin depletion versus partial frataxin dysfunction using zebrafish models

Scientists have identified a family with a rare frataxin gene mutation called R165C, which offers a unique opportunity to study how frataxin works. Unlike most Friedreich’s ataxia (FA) mutations that reduce frataxin levels, R165C leaves the amount of frataxin unchanged but disrupts its ability to interact with the iron-sulfur cluster assembly complex, a key system for mitochondrial health. This difference may explain why the family’s symptoms—such as early vision loss and sensory-motor nerve problems—are atypical for FA. They have mild ataxia and no heart disease, which is usually a hallmark of FA. To investigate, Dr. Van Asperen will create zebrafish models carrying the R165C mutation and compare them to zebrafish completely lacking frataxin. Zebrafish larvae are transparent and display clear, quantifiable movements, allowing real-time imaging of neuronal development and mitochondrial function as well as assessment of motor behavior. This study will reveal whether the R165C mutation affects specific cell types differently and how loss of function versus altered function of frataxin leads to disease. Understanding these mechanisms could guide targeted therapies for FA and related disorders.