Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich’s Ataxia

Mittal Jasoliya, Francesco Sacca, Sunil Sahdeo, Frederic Chedin, Chiara Pane, Vincenzo Brescia Morra, Alessandro Filla, Mark Pook, Gino A Cortopassi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF’s frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich’s therapy.

Original languageEnglish (US)
Article numbere0217776
JournalPloS one
Volume14
Issue number6
DOIs
StatePublished - Jun 1 2019

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Friedreich Ataxia
therapeutics
Gene expression
Gene Expression
gene expression
Transcription
Therapeutics
cells
transcription (genetics)
Dimethyl Fumarate
frataxin
dimethyl fumarate
Mitochondrial Proteins
neurodegenerative diseases
sclerosis
Organelle Biogenesis
Neurodegenerative Diseases
Multiple Sclerosis
Screening
Genes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Dimethyl fumarate dosing in humans increases frataxin expression : A potential therapy for Friedreich’s Ataxia. / Jasoliya, Mittal; Sacca, Francesco; Sahdeo, Sunil; Chedin, Frederic; Pane, Chiara; Morra, Vincenzo Brescia; Filla, Alessandro; Pook, Mark; Cortopassi, Gino A.

In: PloS one, Vol. 14, No. 6, e0217776, 01.06.2019.

Research output: Contribution to journalArticle

Jasoliya, Mittal ; Sacca, Francesco ; Sahdeo, Sunil ; Chedin, Frederic ; Pane, Chiara ; Morra, Vincenzo Brescia ; Filla, Alessandro ; Pook, Mark ; Cortopassi, Gino A. / Dimethyl fumarate dosing in humans increases frataxin expression : A potential therapy for Friedreich’s Ataxia. In: PloS one. 2019 ; Vol. 14, No. 6.
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