Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity

Dentatorubropallidoluysian atrophy (DRPLA) is one of eight autosomal domina nt neurodegenerative disorders characterized by an abnormal CAG repeat expa nsion which results in the expression of a protein with a polyglutamine str etch of excessive length. We have reported recently that four of the gene p roducts (huntingtin, atrophin-1 (DRPLA), ataxin-3, and androgen receptor) a ssociated with these open reading frame triplet repeat expansions are subst rates for the cysteine protease cell death executioners, the caspases, This led us to hypothesize that caspase cleavage of these proteins may represen t a common step in the pathogenesis of each of these four neurodegenerative diseases. Here we present evidence that caspase cleavage of atrophin-1 mod ulates cytotoxicity and aggregate formation. Cleavage of atrophin-1 at Asp( 109) by caspases is critical for cytotoxicity because a mutant atrophin-1 t hat is resistant to caspase cleavage is associated with significantly decre ased toxicity. Further, the altered cellular localization within the nucleu s and aggregate formation associated with the expanded form of atrophin-1 a re completely suppressed by mutation of the caspase cleavage site at Asp(10 9). These results provide support for the toxic fragment hypothesis whereby cleavage of atrophin-1 by caspases may be an important step in the pathoge nesis of DRPLA. Therefore, inhibiting caspase cleavage of the polyglutamine -containing proteins may be a feasible therapeutic strategy to prevent cell death.