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 language | English (US) |
|---|---|
| Article number | e0217776 |
| Journal | PloS one |
| Volume | 14 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2019 |
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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 journal › Article
}
TY - JOUR
T1 - Dimethyl fumarate dosing in humans increases frataxin expression
T2 - A potential therapy for Friedreich’s Ataxia
AU - Jasoliya, Mittal
AU - Sacca, Francesco
AU - Sahdeo, Sunil
AU - Chedin, Frederic
AU - Pane, Chiara
AU - Morra, Vincenzo Brescia
AU - Filla, Alessandro
AU - Pook, Mark
AU - Cortopassi, Gino A
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85066605948&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066605948&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0217776
DO - 10.1371/journal.pone.0217776
M3 - Article
C2 - 31158268
AN - SCOPUS:85066605948
VL - 14
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 6
M1 - e0217776
ER -