Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release

Expansion of CAG repeats within the coding region of target genes is the ca use of several autosomal dominant neurodegenerative diseases including Hunt ington's disease (HD), A hallmark of HD is the proteolytic production of N- terminal fragments of huntingtin containing polyglutamine repeats that form ubiquitinated aggregates in the nucleus and cytoplasm of the affected neur ons. In this study, we used an ecdysone-inducible stable mouse neuro2a cell line that expresses truncated N-terminal huntingtin (tNhtt) with different polyglutamine length, along with mice transgenic for HD exon 1, to demonst rate that the ubiquitin-proteasome pathway is involved in the pathogenesis of HD, Proteasomal 20S core catalytic component was redistributed to the po lyglutamine aggregates in both the cellular and transgenic mouse models. Pr oteasome inhibitor dramatically increased the rate of aggregate formation c aused by tNhtt protein with 60 glutamine (60Q) repeats, but had very little influence on aggregate formation by tNhtt protein with 150Q repeats. Both normal and polyglutamine-expanded tNhtt proteins were degraded by proteasom e, but the rate of degradation was inversely proportional to the repeat len gth. The shift of the proteasomal components from the total cellular enviro nment to the aggregates, as well as the comparatively slower degradation of tNhtt with longer polyglutamine, decreased the proteasome's availability f or degrading other key target proteins, such as p53, This altered proteasom al function was associated with disrupted mitochondrial membrane potential, released cytochrome c from mitochondria into the cytosol and activated cas pase-9- and caspase-9-like proteases These results suggest that the impaire d proteasomal funaction plays an important role in polyglutamine protein-in duced cell death.