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.
Highlights
Friedreich’s Ataxia (FRDA) is an early-onset autosomal recessive disease with an incidence of 1:50000, caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron– sulfur cluster synthesis, iron transfer, and antioxidant defense (Romeo et al, 1983; Dürr et al, 1996; Santos et al, 2010; Vaubel and Isaya, 2013)
To analyze if neurodevelopmental defects may occur in FRDA, we isolated neural stem cells (NSCs) from 13.5 embryonic day of life (E) cortex of KIKO mouse, a well established FRDA animal model, which displays a slowly evolving phenotype despite early biochemical and functional brain deregulations (Lin et al, 2017a,b; Cotticelli et al, 2019), closely resembling patient’s pathologic progression (McMackin et al, 2017)
FRDA clinical symptoms manifest between the first and the second decade of life, patients are exposed to frataxin deficiency since development (Bürk, 2017), presymptomatic defects may contribute to determine the onset and the worsening of FRDA phenotype (Cossée et al, 2000; Santos et al, 2001; Georgiou-Karistianis et al, 2012; Rezende et al, 2016; Selvadurai et al, 2018)
Summary
Friedreich’s Ataxia (FRDA) is an early-onset autosomal recessive disease with an incidence of 1:50000, caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron– sulfur cluster synthesis, iron transfer, and antioxidant defense (Romeo et al, 1983; Dürr et al, 1996; Santos et al, 2010; Vaubel and Isaya, 2013). Even if the progressive degeneration of sensory neurons in the dorsal root ganglia (DRG) and in the dentate nucleus of the cerebellum are observed early upon pathology onset (Bürk, 2017), neuroimaging techniques revealed impairments in white/gray matter structure (Zalesky et al, 2014; Harding et al, 2016; Rezende et al, 2016) and in cerebral functional activation (Georgiou-Karistianis et al, 2012) Reports outlining these defects have been published since a decade (Selvadurai et al, 2018) and several lines of evidence suggest that frataxin deficiency could lead to their insurgence during fetal development (Cossée et al, 2000; Santos et al, 2001; Koeppen et al, 2017). Studies on the pathogenic mechanism underlying FRDA during the neurogenesis are still lacking
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
