Friedreich's ataxia (FRDA) is a
hereditary neurodegenerative disease characterized by a reduced synthesis of the mitochondrial
iron chaperon
protein frataxin as a result of a large GAA triplet-repeat expansion within the first intron of the
frataxin gene. Despite neurodegeneration being the prominent feature of this pathology involving both the central and the peripheral nervous system, information on the impact of
frataxin deficiency in neurons is scant. Here, we describe a neuronal model displaying some major biochemical and morphological features of FRDA. By silencing the mouse NSC34 motor neurons for the
frataxin gene with
shRNA lentiviral vectors, we generated two cell lines with 40% and 70% residual amounts of
frataxin, respectively.
Frataxin-deficient cells showed a specific inhibition of mitochondrial Complex I (CI) activity already at 70% residual
frataxin levels, whereas the
glutathione imbalance progressively increased after silencing. These biochemical defects were associated with the inhibition of cell proliferation and morphological changes at the axonal compartment, both depending on the
frataxin amount. Interestingly, at 70% residual
frataxin levels, the in vivo treatment with the
reduced glutathione revealed a partial rescue of cell proliferation. Thus, NSC34
frataxin silenced cells could be a suitable model to study the effect of
frataxin deficiency in neurons and highlight
glutathione as a potential beneficial therapeutic target for FRDA.