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Chen, K., Lin, G., Haelterman, N.A., Ho, T.S., Li, T., Li, Z., Duraine, L., Graham, B.H., Jaiswal, M., Yamamoto, S., Rasband, M.N., Bellen, H.J. (2016). Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration.  eLife 5(): e16043.
FlyBase ID
FBrf0232938
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC4956409 (PMC) (EuropePMC)
Related Publication(s)
Personal communication to FlyBase

PBac{fh.+3.3} insertions.
Bellen, 2017.1.20, PBac{fh.+3.3} insertions. [FBrf0234522]

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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    eLife
    Title
    eLife
    ISBN/ISSN
    2050-084X
    Data From Reference