Dorsal Root Ganglion neurons as a model of Friedreich Ataxiacellular alterations and therapeutic approaches

Abstract

Friedreich Ataxia (FA) is a neurodegenerative disorder associated with cardiomyopathy caused by decreased levels of frataxin, a mitochondrial protein which function is unknown. It is involved in iron metabolism but this work also shows its role in calcium homeostasis. To study the fundamentals of the disease, our group developed a model based on dorsal root ganglion (DRG) neurons primary cultures to uncover that frataxin deficiency leads to i) mitochondrial depolarisation; ii) decreased levels of NCLX exchanger, slowing down mitochondrial calcium efflux; iii) mitochondrial protein processing/import defects; iv) gene expression changes; v) vitamin D3 metabolism alterations; vi) mitochondrial permeability transition pore (mPTP) opening and vii) cell death. Furthermore, this work includes results obtained with lymphoblastoid cell lines from patients and proposes a drug screening, where compounds replacing/increasing frataxin, chelating calcium, modulating gene expression, inhibiting both mPTP opening and calpains, expand the field of new therapies, highlighting the critical role of calcium in FA.