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The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2008; 105(4):1291-6. DOI: 10.1073/pnas.0711257105
Source: PubMed

ABSTRACT Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders, each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cell-autonomous mechanism and was concomitant with activation of the insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis.

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Available from: Kei Watase, Jun 22, 2015
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    • "There are several neurodegenerative conditions where IGF-I dysfunction is probable. For example, there is evidence of specific disturbances in IGF-I signaling in spinocerebellar ataxia 1 and 7 [8]. Two other ataxic diseases with different etiology and pathology, ataxia telangectasia and Friedreich’s ataxia (FRDA), may also show disturbed IGF-I function. "
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    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. 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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    • "In Alzheimer disease rodent models, over-expression of IGF-1 rescues amyloid b (Ab)-induced cell death [25]. De-regulation of the IGF-1 pathway is observed in both type 1 and type 7 spinocerebellar ataxia (SCA) [26]. IGF-1 signaling is also found to suppress neurodegeneration in type 1 spinocerebellar ataxia and Huntington's disease [27] [28]. "
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