The AAA proteins (ATPases associated with diverse cellular activities) constitute a subfamily of the Walker-type NTPases. These proteins contain a conserved ATPase domain, typically spanning 200-250 residues and including Walker motifs A and B and the SRH (second region of homology) motif. They participate in diverse cellular processes including protein folding and unfolding, assembly and disassembly of protein complexes, protein transport through membrane fusion and protein degradation. The AAA proteins are well conserved from prokaryotes to human. C. elegans possesses 24 members of AAA proteins. Some of these proteins are homologous to those involved in human genetic diseases such peroxisome diseases and hereditary spastic paraplegia.Recent reports have demonstrated a direct role for the molecular chaperones HDJ-1, HDJ-2 and Hsp104 in preventing polyglutamine aggregate formation, which can cause a neurodegenerative disorder. It has also been reported that
p97/VCP, a member of AAA family proteins, can bind to the longer polyglutamine tract. In C. elegans,
p97/VCP homologues, C41C4.8 and C06A1.1, and closely related AAA proteins such as MAC-1 have been identified, whereas no homologue of Hsp104 has been identified. Co-expression of yeast Hsp104 was demonstrated to be able to reverse the toxic effect of polyglutamine expression and the formation of aggregates. In this presentation, we will show effects of C41C4.8 and C06A1.1 on polyglutamine aggregate formation.RNAi assays revealed that simultaneous disruption of both homologues was embryonic lethal, although single disruption had no detectable defect, suggesting that their cellular functions are redundant. It is important to note that C. elegans possesses two highly similar homologues of
p97/VCP, while human and mouse possess only one. The polyglutamine repeats were expressed as green fluorescent protein (GFP) - fusion proteins in the body wall muscle cells using the well-characterized
unc-54 promoter. When the repeats were longer than 40, discrete cytoplasmic aggregates were formed and already appeared early in embryogenesis. The formation of aggregates did not affect on motility of young adult transgenic animals and on life span. Aggregate formation was partially but significantly suppressed by co-expression of C41C4.8, C06A1.1 or MAC-1. These suggest that
p97/VCP homologues, AAA chaperones, play a crucial role in controlling polyglutamine aggregation.