Abstract
Loss-of-function mutations in the gene (CSTB) encoding human cystatin B, a widely expressed cysteine protease inhibitor, are responsible for a severe neurological disorder known as Unverricht-Lundborg disease (EPM1). The primary cellular events and mechanisms underlying the disease are unknown. We found that mice lacking cystatin B develop myoclonic seizures and ataxia, similar to symptoms seen in the human disease. The principal cytopathology appears to be a loss of cerebellar granule cells, which frequently display condensed nuclei, fragmented DNA and other cellular changes characteristic of apoptosis. This mouse model of EPM1 provides evidence that cystatin B, a non-caspase cysteine protease inhibitor, has a role in preventing cerebellar apoptosis.
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Acknowledgements
We thank D. Cox, D. Vollrath, C. Prange Pennacchio, C. Iannicola, C. Karlovich, G. Barsh and members of the Myers laboratory for discussions and support, F. Davies for use of the rotorod, A. Nagy for the R1 ES cells donation, N. Ghouri for EM sample preparation, S. Krajewski for assistance with EM interpretations and C. Davis for his help with ECoG recordings. This work is supported by grant NIH NS29709 and HD24064 (J.L.N.).
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Pennacchio, L., Bouley, D., Higgins, K. et al. Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nat Genet 20, 251–258 (1998). https://doi.org/10.1038/3059
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DOI: https://doi.org/10.1038/3059
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