title: Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration.
abstract: Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Kuchuan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Guang
authors.initials: G
authors.lastname: Lin
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Nele A
authors.initials: NA
authors.lastname: Haelterman
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.
authors.forename: Tammy Szu-Yu
authors.initials: TS
authors.lastname: Ho
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Tongchao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
authors.forename: Lita
authors.initials: L
authors.lastname: Duraine
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Brett H
authors.identifier: 0000-0001-8451-8154
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
authors.forename: Manish
authors.initials: M
authors.lastname: Jaiswal
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.|Department of Neuroscience, Baylor College of Medicine, Houston, United States.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Rasband
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
authors.forename: Hugo J
authors.identifier: 0000-0001-5992-5989
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D005621:Friedreich Ataxia / Q000503:physiopathology*; D007501:Iron / Q000633:toxicity*; D033862:Iron-Binding Proteins / Q000235:genetics*; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D013107:Sphingolipids / Q000096:biosynthesis*; D000096923:Frataxin
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D029721:Drosophila Proteins; D007501:Iron; D033862:Iron-Binding Proteins; D018006:Myogenic Regulatory Factors; D013107:Sphingolipids; D000096923:Frataxin; C499409:Mef2 protein, Drosophila; C578560:Pdk1 protein, Drosophila
keywords: D. melanogaster; Friedreich's ataxia; Mef2; Pdk1; frataxin; iron; neuroscience; sphingolipid