Dentatorubral pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder. It is associated with an abnormal CAG repeat expansion resulting in formation of a protein with an elongated polyglutamine stretch. However, neither the physiological roles of the DRPLA gene product nor molecular mechanisms of its pathogenesis have yet been elucidated. Here we report that the DRPLA protein is cleaved at a site near the N terminus during apoptosis induced by VP-16, staurosporine, or glucocorticoid. Moreover, the in vitro translated DRPLA protein is cleaved by recombinant caspase-3, a member of the cysteine protease family, which is thought to be a main executioner of apoptosis. Using mutant DRPLA proteins, the cleavage site was identified as 106 DSLDG 110 . The cleavage, however, was not modulated by the length of the polyglutamine stretch. These findings suggest that the DRPLA protein is one of the physiological substrates of caspase-3, and its cleavage may result in structural and biochemical alterations associated with apoptosis.

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