Friedreich's ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction occurs before the death of proprioceptive neurons in a dying-back process. This group investigated how the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes a sequence of events that lead to neuronal death. These observations support the author's proposed model of FRDA distal axonopathy based on axonal focal damage. The group link this damage to the formation of "axonal spheroids," formation of which also correlated with oxidative stress and changes in calcium signaling. The authors suggest that axonal spheroids may be a consequence of calcium imbalance, thus that the quenching or removal extracellular Ca2+ to prevent spheroids formation might reduce disease progression. In their neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration.
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