CASPASE CLEAVAGE OF GENE-PRODUCTS ASSOCIATED WITH TRIPLET EXPANSION DISORDERS GENERATES TRUNCATED FRAGMENTS CONTAINING THE POLYGLUTAMINE TRACT

The neurodegenerative diseases Huntington disease, dentatorubropallido luysian atrophy, spinocerebellar atrophy type 3, and spinal bulbar mus cular atrophy are caused by expansion of a polyglutamine tract within their respective gene products. There is increasing evidence that gene ration of truncated proteins containing an expanded polyglutamine trac t may be a key step in the pathogenesis of these disorders. We now rep ort that, similar to huntingtin, atrophin-1, ataxin-3, and the androge n receptor are cleaved in apoptotic extracts. Furthermore, each of the se proteins is cleaved by one or more purified caspases, cysteine prot eases involved in apoptotic death. The CAG length does not modulate su sceptibility to cleavage of any of the full-length proteins. Our resul ts suggest that by generation of truncated polyglutamine-containing pr oteins, caspase cleavage may represent a common step in the pathogenes is of each of these neurodegenerative diseases.