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

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.

• Authors: Jin Zhong, Jixian Deng, Jennifer Phan, Stephen Dlouhy, Huangbing Wu, Weiguo Yao, Ping Ye, A Joseph D'Ercole, Wei-Hua Lee
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 80 Issue 4 Pg. 481-90 (May 15 2005) ISSN: 0360-4012 [Print] United States
• PMID: 15846777 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Insulin-Like Growth Factor I
• DNA Polymerase I
• Casp3 protein, mouse
• Caspase 3
• Caspases
• Bromodeoxyuridine

Topics

• Age Factors
• Animals
• Animals, Newborn
• Apoptosis (drug effects)
• Ataxia (pathology, physiopathology)
• Behavior, Animal
• Bromodeoxyuridine
• Caspase 3
• Caspases (metabolism)
• Cell Count (methods)
• Cerebellum (cytology)
• DNA Polymerase I (metabolism)
• Gene Expression Regulation, Developmental
• In Situ Hybridization (methods)
• Insulin-Like Growth Factor I (genetics, pharmacology)
• Mice
• Mice, Neurologic Mutants
• Mice, Transgenic
• Motor Activity (drug effects, physiology)
• Neurons (cytology, drug effects)
• Psychomotor Performance (drug effects, physiology)