At least eight hereditary neurodegenerative disorders, including Huntington's Disease, have been identified in which the disease locus expresses a protein that contains an expanded glutamine tract. We have previously established a model system for studying polyglutamine (polyQ) neurotoxicity in C. elegans (PNAS 96, 179-184, 1999). The N-terminus of the mutant human huntingtin protein, which contains an expanded glutamine tract, is expressed in the well-characterized ASH neurons. Expression of the expanded huntingtin polyglutamine tract leads to age-dependent degeneration of the ASH neurons. To identify genes that normally protect neurons from polyQ-mediated neurodegeneration, we performed an F2 EMS screen for mutations in genes that enhanced polyQ toxicity in ASH neurons. Seven strains were isolated that carried mutations in a previously uncharacterized gene,
pqe-1 (polyQ enhancer-1). Differential splicing of
pqe-1 results in at least three nuclear localized PQE-1 proteins. PQE-1A and PQE-1B contain a putative exonuclease domain. PQE-1A and PQE-1C contain a large glutamine/proline-rich domain which is essential for
pqe-1 function (PNAS 99, 17131-6, 2002). To understand the relationship between polyglutamine toxicity and
pqe-1 function, we plan to use a yeast two hybrid screen to identify PQE-1 interacting factors. Currently, we are determining the smallest region of PQE-1 necessary to protect ASH neurons from polyQ insults. Two genetic approaches are underway to identify additional genes that modulate polyQ toxicity. First, we are using RNA interference (RNAi) to systematically target genes that protect neurons from polyQ-mediated neurodegeneration. We are focusing on those genes whose decrease in function results in sterility or reduced viability, since these candidates may have been missed in the original F2 EMS screen described above. To identify genes that are required for poly-Q mediated neurodegeneration, we also performed a genetic screen to isolate mutations that suppress polyQ-mediated ASH neurodegeneration. Identification and characterization of genes isolated from these collective approaches will provide insight into pathogenic mechanisms underlying polyQ-induced neurodegeneration.