Abstract
Oxidative stress is actively involved in Friedreich’s Ataxia (FA), thus pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor Nrf2 on frataxin-deficient cultured motor neurons and on fibroblasts of patients. The in vitro treatment of the potent Nrf2 activator sulforaphane increased Nrf2 protein levels and led to the upregulation of phase II antioxidant enzymes. The neuroprotective effects were accompanied by an increase in neurites’ number and extension. Sulforaphane (SFN) is a natural compound of many diets and is now being used in clinical trials for other pathologies. Our results provide morphological and biochemical evidence to endorse a neuroprotective strategy that may have therapeutic relevance for FA. The findings of this work reinforce the crucial importance of Nrf2 in FA and provide a rationale for using Nrf2-inducers as pharmacological agents.
Highlights
Oxidative stress and mitochondrial dysfunction play a critical role in the pathogenesis of Friedreich’s Ataxia (FA), an autosomal-recessive neurodegenerative disease due to homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9
We determined whether NF-E2-related factor-2 (Nrf2), master regulator of redox homeostasis, might be a therapeutic target for the disease
Variations in the intracellular redox state can, transiently modify the activity of Nrf2 and its activation has been shown to counteract a number of pathological mechanisms associated with several neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis, Huntington’s disease and Multiple Sclerosis [9]
Summary
Oxidative stress and mitochondrial dysfunction play a critical role in the pathogenesis of Friedreich’s Ataxia (FA), an autosomal-recessive neurodegenerative disease due to homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9. Nrf modulates the expression of many genes involved in the antioxidant defense by the activation of the enzymes constituting the phase II response [4]. We chose sulforaphane (SFN) to target Nrf in a frataxin-silenced model of cultured motor neurons generated and characterized in our laboratory [13,14]. Our findings indicate that both Nrf2-inducers significantly up-regulate Nrf and its target genes in frataxin-deficient motor neurons. This activation contributes to stabilizing the redox environment in FA by targeting the repletion of reduced glutathione (GSH) and mitigating reactive oxygen species (ROS)-related damage, counteracting the neurodegeneration
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