Abstract
Friedreich’s ataxia is the most common hereditary ataxia for which there is no cure or approved treatment at present. However, therapeutic developments based on the understanding of pathological mechanisms underlying the disease have advanced considerably, with the implementation of cellular models that mimic the disease playing a crucial role. Human olfactory ecto-mesenchymal stem cells represent a novel model that could prove useful due to their accessibility and neurogenic capacity. Here, we isolated and cultured these stem cells from Friedreich´s ataxia patients and healthy donors, characterizing their phenotype and describing disease-specific features such as reduced cell viability, impaired aconitase activity, increased ROS production and the release of cytokines involved in neuroinflammation. Importantly, we observed a positive effect on patient-derived cells, when frataxin levels were restored, confirming the utility of this in vitro model to study the disease. This model will improve our understanding of Friedreich´s ataxia pathogenesis and will help in developing rationally designed therapeutic strategies.
Highlights
Friedreich’s ataxia (FRDA, OMIM229300), the most common hereditary ataxia among Caucasians, is predominantly a neurodegenerative disease affecting the dorsal root ganglia, spinal cord, brainstem and cerebellum [1], with extra-neurological manifestations such as hypertrophic cardiomyopathy [2] and diabetes mellitus [3]
We investigated the phenotype of human olfactory mucosa stem cells derived from healthy donors and FRDA patients, aiming to characterize them and to test whether they might serve as an in vitro model to study the etiopathogenesis of FRDA
Cells were positive for Stro-1, one of the best-known markers of mesenchymal stem cells (MSCs) [32], and for Nestin and neuron-glial antigen 2 (NG2), two neural stem cell markers, already described as exhibited by this type of mucosa-derived cells as they originate from the neural crest [33]
Summary
Friedreich’s ataxia (FRDA, OMIM229300), the most common hereditary ataxia among Caucasians, is predominantly a neurodegenerative disease affecting the dorsal root ganglia, spinal cord, brainstem and cerebellum [1], with extra-neurological manifestations such as hypertrophic cardiomyopathy [2] and diabetes mellitus [3]. The majority of FRDA patients have an abnormal expansion of the triplet GAA inside the first intron of the FXN gene [5] This expansion causes a reduction in the expression of the protein [6,7] by formation of a non-B DNA structure, persistent RNA–DNA hybrids or heterochromatin formation [8]. There are different biological functions in which frataxin plays an important role, including iron homeostasis, iron–sulphur cluster biosynthesis, modulation of oxidative phosphorylation and regulation of the response to oxidative stress. It is still not known how frataxin deficiency triggers the neurodegenerative process associated with the disease (for a review of frataxin function, see [10,11])
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