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Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor

Amelié Hu, Myriam Rai, Simona Donatello, View ORCID ProfileMassimo Pandolfo
doi: https://doi.org/10.1101/221242
Amelié Hu
1Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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Myriam Rai
1Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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Simona Donatello
1Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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Massimo Pandolfo
1Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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  • ORCID record for Massimo Pandolfo
  • For correspondence: massimo.pandolfo@ulb.ac.be
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Abstract

Epigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at the FXN locus is the key pathogenic event in Friedreich ataxia (FRDA), a recessive neurodegenerative and systemic disease. FXN is involved in iron-sulfur (Fe-S) cluster biogenesis in mitochondria, its deficiency causes multiple Fe-S protein deficiencies, mitochondrial dysfunction and oxidative stress. Primary sensory neurons (PSNs) in the dorsal root ganglia (DRGs) are the most vulnerable cells in FRDA, whose abnormal development and degeneration leads to the onset and early progression of ataxia. We generated PSNs from induced pluripotent stem cells (iPSCs) from FRDA patients and showed that they recapitulate the key pathogenic events in FRDA, including low FXN levels, loss of Fe-S proteins and impaired antioxidant responses. We also showed that FXN deficiency in these cells may be partially corrected by a pimelic benzamide histone deacetylase inhibitor, a class of potential therapeutics for FRDA. We generated and validated a cellular model of the most vulnerable neurons in FRDA, which can be used for further studies on pathogenesis and treatment approaches.

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Posted November 17, 2017.
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Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor
Amelié Hu, Myriam Rai, Simona Donatello, Massimo Pandolfo
bioRxiv 221242; doi: https://doi.org/10.1101/221242
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Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor
Amelié Hu, Myriam Rai, Simona Donatello, Massimo Pandolfo
bioRxiv 221242; doi: https://doi.org/10.1101/221242

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