Participation of Par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid

Huntington's disease (HD) is a progressive neurodegenerative disorder chara cterized by chorea, psychiatric disturbances, and dementia. It is caused by a polyglutamine repeat expansion in the huntingtin protein. The striatum i s a major site of neuronal loss in HD, but the mechanisms underlying the ne urodegenerative process have not been established. Systemic administration of the succinate dehydrogenase inhibitor 3-nitropropionic acid (3NP) to rod ents results in motor dysfunction and degeneration of striatal neurons with features similar to those of HD. Here we report that levels of prostate ap optosis response-4 (Par-4; a protein recently linked to neuronal apoptosis) increase in striatum, and to a lesser extent in cortex and hippocampus, af ter systemic administration of 3NP to adult rats. The increase in Par-4 lev els occurred within 6 h of 3NP administration and was followed by an increa se in caspase activation which preceded neuronal loss. Exposure of cultured primary striatal neurons to 3NP induced a rapid increase of Par-4 levels a nd caspase activation. Treatment of striatal neurons with a Par-4 antisense oligonucleotide blocked Par-4 induction by 3NP, suppressed caspase activat ion, and attenuated neuronal apoptosis. The caspase-3 inhibitor DEVD suppre ssed SNP-induced apoptosis of striatal neurons, but did not prevent inducti on of Par-4, indicating that Par-4 acts upstream of caspase-3 activation in the cell death pathway. Our results suggest that Par-4 plays an important role in the degeneration of striatal neurons in an experimental model of HD . (C) 2000 Academic Press.