Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration.

Autor:	Chen K; Program in Developmental Biology, Baylor College of Medicine, Houston, United States., Lin G; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States., Haelterman NA; Program in Developmental Biology, Baylor College of Medicine, Houston, United States., Ho TS; Department of Neuroscience, Baylor College of Medicine, Houston, United States., Li T; Program in Developmental Biology, Baylor College of Medicine, Houston, United States., Li Z; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States., Duraine L; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States., Graham BH; Program in Developmental Biology, Baylor College of Medicine, Houston, United States.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States., Jaiswal M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States., Yamamoto S; 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., Rasband MN; Program in Developmental Biology, Baylor College of Medicine, Houston, United States.; Department of Neuroscience, Baylor College of Medicine, Houston, United States., Bellen HJ; 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.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2016 Jun 25; Vol. 5. Date of Electronic Publication: 2016 Jun 25.
DOI:	10.7554/eLife.16043
Abstrakt:	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.
Databáze:	MEDLINE
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