Abstract | BACKGROUND: 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. CONCLUSION: 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.
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Authors | Carolina Franco, Silvia Fernández, Ignacio Torres-Alemán |
Journal | Molecular neurodegeneration
(Mol Neurodegener)
Vol. 7
Pg. 51
(Oct 05 2012)
ISSN: 1750-1326 [Electronic] England |
PMID | 23039828
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Iron-Binding Proteins
- frataxin
- Insulin-Like Growth Factor I
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Topics |
- Animals
- Astrocytes
(metabolism)
- Cells, Cultured
- Female
- Friedreich Ataxia
(metabolism)
- Humans
- Insulin-Like Growth Factor I
(metabolism, pharmacology)
- Iron-Binding Proteins
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neurons
(metabolism)
- Real-Time Polymerase Chain Reaction
- Signal Transduction
(physiology)
- Transfection
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