Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor.
We employed induced pluripotent stem cell (iPSC)-derived neurons obtained from Friedreich ataxia (FRDA) patients and healthy subjects, FRDA neurons and CT neurons, respectively, to unveil phenotypic alterations related to frataxin (FXN) deficiency and investigate if they can be reversed by treatments that upregulate FXN. FRDA and control iPSCs were equally capable of differentiating into a neuronal or astrocytic phenotype. FRDA neurons showed lower levels of iron–sulfur (Fe–S) and lipoic acid-containing proteins, higher labile iron pool (LIP), higher expression of mitochondrial superoxide dismutase (SOD2), increased reactive oxygen species (ROS) and lower reduced glutathione (GSH) levels, and enhanced sensitivity to oxidants compared with CT neurons, indicating deficient Fe–S cluster biogenesis, altered iron metabolism, and oxidative stress. Treatment with the benzamide HDAC inhibitor 109 significantly upregulated FXN expression and increased Fe–S and lipoic acid-containing protein levels, downregulated SOD2 levels, normalized LIP and ROS levels, and almost fully protected FRDA neurons from oxidative stress-mediated cell death. Our findings suggest that correction of FXN deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.
IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy,
Franca
F
Codazzi
Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
Amelié
A
Hu
Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
Myriam
M
Rai
Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
Simona
S
Donatello
IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Floramarida
F
Salerno Scarzella
IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Elisabeth
E
Mangiameli
IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Ilaria
I
Pelizzoni
IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy,
Fabio
F
Grohovaz
Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
Massimo
M
Pandolfo
D001549:Benzamides / Q000494:pharmacology; D005621:Friedreich Ataxia / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D013482:Superoxide Dismutase / Q000378:metabolism; D008063:Thioctic Acid / Q000378:metabolism; D000096923:Frataxin; D000099156:Superoxide Dismutase 2
D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D013482:Superoxide Dismutase; D008063:Thioctic Acid; D000096923:Frataxin; D000099156:Superoxide Dismutase 2