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Nrf2 Induction Re-establishes a Proper Neuronal Differentiation Program in Friedreich's Ataxia Neural Stem Cells
Piergiorgio La Rosa1, Marta Russo1, Jessica D'Amico1
1Unit of Neuromuscular and Neurodegenerative Diseases, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
Abstract:
Frataxin deficiency is the pathogenic cause of Friedreich's Ataxia, an autosomal recessive disease characterized by the increase of oxidative stress and production of free radicals in the cell. Although the onset of the pathology occurs in the second decade of life, cognitive differences and defects in brain structure and functional activation are observed in patients, suggesting developmental defects to take place during fetal neurogenesis. Here, we describe impairments in proliferation, stemness potential and differentiation in neural stem cells (NSCs) isolated from the embryonic cortex of the Frataxin Knockin/Knockout mouse, a disease animal model whose slow-evolving phenotype makes it suitable to study pre-symptomatic defects that may manifest before the clinical onset. We demonstrate that enhancing the expression and activity of the antioxidant response master regulator Nrf2 ameliorates the phenotypic defects observed in NSCs, re-establishing a proper differentiation program.
Insights
Frataxin deficiency causes Friedreich
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Frataxin deficiency underlies Friedreich's Ataxia, a neurodegenerative disorder.
- Oxidative stress and free radical production are hallmarks of the disease.
- Pre-symptomatic developmental defects in neurogenesis may occur.
Purpose of the Study:
- To investigate impairments in neural stem cells (NSCs) from an early-stage Friedreich's Ataxia mouse model.
- To explore the role of the antioxidant regulator Nrf2 in mitigating these defects.
Main Methods:
- Isolation and analysis of neural stem cells (NSCs) from embryonic Frataxin Knockin/Knockout mouse cortex.
- Assessment of NSC proliferation, stemness, and differentiation.
- Evaluation of Nrf2 expression and activity modulation.
Main Results:
- NSCs from the Frataxin mouse model exhibit impaired proliferation, stemness, and differentiation.
- Enhancing Nrf2 expression and activity in these NSCs rescues the observed phenotypic defects.
- Nrf2 activation restores a proper differentiation program in affected NSCs.
Conclusions:
- Frataxin deficiency impacts fetal neurogenesis, leading to NSC dysfunction.
- Nrf2 is a key regulator that can ameliorate these pre-symptomatic defects.
- Targeting Nrf2 may offer therapeutic strategies for Friedreich's Ataxia.
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