Abstract
Friedreich’s ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca2+ to prevent spheroids formation. In our 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.
Highlights
Friedreich’s ataxia (FRDA) is a neurodegenerative disease characterized by progressive limb and gait ataxia associated with hypertrophic cardiomyopathy and diabetes mellitus
We show that chronic frataxin deficiency induces the failure of mitochondria involving oxidative stress and improper calcium handling, which are responsible for axonal dystrophy and the impairment of axonal transport and autophagic flux
Primary cultures of dorsal root ganglia (DRG) were labeled with Mitotracker at 5 days in vitro (DIV) and the frataxin-deficient neurons exhibited axonal swelling and spheroid formation that retained a great amount of mitochondria, in a completely different pattern than observed in control neurons (Figure 1A)
Summary
Friedreich’s ataxia (FRDA) is a neurodegenerative disease characterized by progressive limb and gait ataxia associated with hypertrophic cardiomyopathy and diabetes mellitus. Pathological changes appear in the dorsal root ganglia (DRG) and sensory peripheral nerves leading to gait ataxia. Peripheral neuropathy consists of hypomyelination and axonal loss of large myelinated sensory neurons of DRG with slowly dying-back degeneration (Morral et al, 2010; Koeppen, 2013). Throughout the disease course, neuronal destruction becomes manifest by a loss of cell body sensory neurons, mainly the proprioceptive neurons (Koeppen and Mazurkiewicz, 2013). Mutations in the frataxin gene (FXN) gene are responsible for the disease. In 98% of patients this disorder is caused by the homozygous GAA-triplet repeat expansion (Campuzano et al, 1997) in the FXN first intron associated with epigenetic changes (Festenstein, 2006) affects transcription and reduce the amount of frataxin in all tissues. Frataxin is a small protein of 23 kDa which is associated with the mitochondrial inner membrane (Campuzano et al, 1997)
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