Abstract
In the search for neuroprotective factors in Huntington's disease, we found that insulin growth factor 1 via activation of the serine/threonine kinase Akt/PKB is able to inhibit neuronal death specifically induced by mutant huntingtin containing an expanded polyglutamine stretch. The IGF-1/Akt pathway has a dual effect on huntingtin-induced toxicity, since activation of this pathway also results in a decrease in the formation of intranuclear inclusions of mutant huntingtin. We demonstrate that huntingtin is a substrate of Akt and that phosphorylation of huntingtin by Akt is crucial to mediate the neuroprotective effects of IGF-1. Finally, we show that Akt is altered in Huntington's disease patients. Taken together, these results support a potential role of the Akt pathway in Huntington's disease.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cell Death
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Cells, Cultured
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Corpus Striatum / cytology
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Enzyme Activation
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Humans
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Huntingtin Protein
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Huntington Disease / genetics
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Huntington Disease / pathology*
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Inclusion Bodies / metabolism
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Insulin-Like Growth Factor I / metabolism*
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurons / cytology*
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Neurons / metabolism
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphorylation
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Point Mutation
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Recombinant Fusion Proteins / metabolism
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Substrate Specificity
Substances
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HTT protein, human
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Huntingtin Protein
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Nerve Tissue Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Insulin-Like Growth Factor I
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt