The effect of expressing human huntingtin fragments containing polyglutamine (polyQ) tracts of varying lengths was assessed in Caenorhabditis elegans ASH sensory neurons in young and old animals. Expression of a huntingtin fragment containing a polyQ tract of 150 residues (Htn-Q150) led to progressive ASH neurodegeneration but did not cause cell death. Progressive cell death and enhanced neurodegeneration were observed in ASH neurons that coexpressed Htn-Q150 and a subthreshold dose of a toxic OSM-10::green f luorescent protein (OSM-10::GFP) fusion protein. Htn-Q150 huntingtin protein fragments formed protein aggregates in ASH neurons, and the number of ASH neurons containing aggregates increased as animals aged. ASH neuronal cell death required ced-3 caspase function, indicating that the observed cell death is apoptotic. Of interest, ced-3 played a critical role in Htn-Q150-mediated neurodegeneration but not in OSM10::GFP-mediated ASH neurodegeneration. ced-3 function was important but not essential for the formation of protein aggregates. Finally, behavioral assays indicated that ASH neurons, coexpressing Htn-Q150 and OSM10::GFP, were functionally impaired at 3 days before the detection of neurodegeneration, cell death, and protein aggregates.Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative human disorder caused by pathological expansion of a CAG repeat, encoding polyglutamine (polyQ), in the HD gene (1). HD pathology is restricted to the central nervous system, despite widespread expression of huntingtin (2), and results in progressive brain atrophy as well as selective neuronal cell loss, particularly in the striatum and deep layers of the frontal cortex (3, 4). The length of the mutant CAG repeat correlates with age of neurological onset with typical HD alleles of 40-50 codons leading to midlife onset of the disease (1, 5). In addition to HD, seven other dominant polyQ neurodegenerative diseases have been identified, including spinobulbar muscular atrophy (6), dentatorubropallidoluysian atrophy (7), and several spinocerebellar ataxias (spinocerebellar ataxia 1,2,3,6,7) (8-14). Because the proteins encoded by these loci share no structural similarity outside the polyQ tract (15), the polyQ tract itself has been implicated in driving the disease process with a modulatory role for protein context.Although the pathogenic mechanism of HD and the other polyQ-mediated diseases is unknown, polyQ expansion alters the physical properties of the mutant huntingtin, as evidenced by decreased mobility on SDS͞PAGE and increased reactivity with specific monoclonal reagents (16,17). Aberrant behavior of mutant huntingtin also results in the formation of cytoplasmic aggregates and intranuclear inclusion bodies in HD brains (18). Intranuclear inclusion bodies contain N-terminally truncated fragments of huntingtin, based on antibody studies. Recently, in vitro evidence for a ''toxic fragment'' model of HD has been obtained. A mouse model partially replicating HD was described by using ...