Abstracts

RATIONALE: We previously used linkage analysis and positional cloning techniques to determine that loss-of-function mutations in the gene encoding the cysteine protease inhibitor cystatin B are responsible for Unverricht-Lundborg progressive myoclonus epilepsy (EPM1). Since then, we have constructed mice lacking cystatin B that accurately model EPM1 to aid in the biochemical characterization of this disease. Although it is known that cystatin B inhibits a class of lysosomal proteases called cathepsins in vitro, it remains to be established how the absence of this protein causes the seizures, ataxia and myoclonus characteristic of this disease.
METHODS: We have used genetic and biochemical techniques in an effort to determine how the loss of regulation of cathepsins by cystatin B leads to the neuronal apoptosis characteristic of EPM1. By removing cathepsins one by one from cystatin B-deficient mice and testing for rescue of the mutant phenotype, we are attempting to identify the cathepsin or cathepsins involved in this degenerative process.
RESULTS: We do not detect any changes in phenotype or amount of apoptosis in mice lacking both cystatin B and cathepsin S, arguing against the hypothesis that overactivity of cathepsin S is responsible for the EPM1-like phenotypes. We are currently testing other cathepsins for their involvement in this disease.
CONCLUSIONS: If, as we suspect, the disregulation of a particular cathepsin contributes to the symptoms of EPM1 by inducing neuronal apoptosis, this work may help identify a new entry point into the apoptotic pathway. Not only would this finding be of interest to the study of apoptosis, it may also lead to advances in the treatment of other epilepsies.
Support: Epilepsy Foundation Postdoctoral Fellowship to MKH, NIH training grant HG 00044-05 to RMM.