Insulin-like growth factor-I protects granule neurons from apoptosis and improves ataxia in weaver mice

Jin Zhong, Jixian Deng, Jennifer Phan, Stephen Dlouhy, Huangbing Wu, Weiguo Yao, Ping Ye, A. Joseph D'Ercole, Wei Hua Lee

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Most cerebellar granule neurons in weaver mice undergo premature apoptosis during the first 3 postnatal weeks, subsequently leading to severe ataxia. The death of these granule neurons appears to result from a point mutation in the GIRK2 gene, which encodes a G protein-activated, inwardly rectifying K + channel protein. Although the genetic defect was identified, the molecular mechanism by which the mutant K+ channel selectively attacks granule neurons in weaver mice is unclear. Before their demise, weaver granule neurons express abnormally high levels of insulin-like growth factor (IGF) binding protein 5 (IGFBP5). IGF-I is essential for the survival of cerebellar neurons during their differentiation. Because IGFBP5 has the capacity to block IGF-I activity, we hypothesized that reduced IGF-I availability resulting from excess IGFBP5 accelerates the apoptosis of weaver granule neurons. We found that, consistently with this hypothesis, exogenous IGF-I partially protected cultured weaver granule neurons from apoptosis by activating Akt and decreasing caspase-3 activity. To determine whether IGF-I protects granule neurons in vivo, we cross-bred weaver mice with transgenic mice that overexpress IGF-I in the cerebellum. The cerebellar volume was increased in weaver mice carrying the IGF-I transgene, predominantly because of an increased number of surviving granule neurons. The presence of the IGF-I transgene resulted in improved muscle strength and a reduction in ataxia, indicating that the surviving granule neurons are functionally integrated into the cerebellar neuronal circuitry. These results confirm our previous suggestion that a lack of IGF-I activity contributes to apoptosis of weaver granule neurons in vivo and supports IGF-I's potential therapeutic use in neurodegenerative disease.

Original languageEnglish (US)
Pages (from-to)481-490
Number of pages10
JournalJournal of Neuroscience Research
Volume80
Issue number4
DOIs
StatePublished - May 15 2005

Keywords

  • Granule neurons
  • IGF-I
  • Potassium channel
  • Weaver mice

ASJC Scopus subject areas

  • Neuroscience(all)

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