title: Frataxin deficiency unveils cell-context dependent actions of insulin-like growth factor I on neurons.
abstract: BACKGROUND
  Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by deficiency of the mitochondrial iron chaperone frataxin (Fxn). FRDA has no cure, but disease-modifying strategies to increase frataxin are under study. Because insulin-like growth factor I (IGF-I) has therapeutic effects in various types of cerebellar ataxia and exerts protective actions on mitochondrial function, we explored the potential Fxn-stimulating activity of this growth factor on brain cells.
  
  
  RESULTS
  IGF-I normalized frataxin levels in frataxin-deficient neurons and astrocytes through its canonical Akt/mTOR signaling pathway. IGF-I also stimulated frataxin in normal astrocytes but not in normal neurons, whereas IGF-I stimulated the Akt/mTOR pathway in both types of cells. This cell context-dependent action of IGF-I on neurons suggested that the intrinsic regulation of Fxn in neurons is different than in astrocytes. Indeed, neurons express much higher levels of frataxin and are much more sensitive to Fxn deficiency than astrocytes; i.e.: only neurons die in the absence of frataxin. In addition, the half-life of frataxin is shorter in neurons than in astrocytes, while after blockade of the proteasome only neurons responded to IGF-I with an increase in frataxin levels. We also explore a potential therapeutic utility of IGF-I in FRDA-like transgenic mice (YG8R mice) and found that treatment with IGF-I normalized motor coordination in these moderately ataxic mice.
  
  
  CONCLUSIONS
  Exposure to IGF-I unveiled a cell-specific regulation of frataxin in neurons as compared to astrocytes. Collectively, these results indicate that IGF-I exerts cell-context neuroprotection in frataxin deficiency that maybe therapeutically effective.
authors.affiliation: Cajal Institute, CSIC, and CIBERNED, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Franco
authors.forename: Silvia
authors.initials: S
authors.lastname: Fernández
authors.forename: Ignacio
authors.initials: I
authors.lastname: Torres-Alemán
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005621:Friedreich Ataxia / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D033862:Iron-Binding Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D000096923:Frataxin
chemical_list: D007334:Insulin-Like Growth Factor I; D033862:Iron-Binding Proteins; D000096923:Frataxin