DENTATORUBRAL PALLIDOLUYSIAN ATROPHY (DRPLA) PROTEIN IS CLEAVED BY CASPASE-3 DURING APOPTOSIS

Dentatorubral pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder. It is associated with an abnormal CAG repe at expansion resulting in formation of a protein with an elongated pol y glutamine stretch, However, neither the physiological roles of the D RPLA gene product nor molecular mechanisms of its pathogenesis have ye t been elucidated. Here we report that the DRPLA protein is cleaved at a site near the N terminus during apoptosis induced by VP-16, stauros porine, or glucocorticoid. Moreover, the in vitro translated DRPLA pro tein is cleaved by recombinant caspase-3, a member of the cysteine pro tease 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 prote in is one of the physiological substrates of caspase-3, and its cleava ge may result in structural and biochemical alterations associated wit h apoptosis.