Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from huntingtin polyglutamine neurotoxicity.
Huntington's disease is a progressive neurodegenerative disease caused by a polyglutamine (polyQ) repeat expansion in the huntingtin protein [Huntington's Disease Collaborative Research Group (1993) Cell 72, 971-983]. To understand the mechanism by which polyQ repeats cause neurodegeneration and cell death, we modeled polyQ neurotoxicity in Caenorhabditis elegans. In our model, expression of N-terminal fragments of human huntingtin causes polyQ-dependent degeneration of neurons. We conducted a genetic screen to identify proteins that protect neurons from the toxic effects of expanded polyQ tracts. Loss of polyQ enhancer-1 (pqe-1) gene function strongly and specifically exacerbates neurodegeneration and cell death, whereas overexpression of a pqe-1 cDNA protects C. elegans neurons from the toxic effects of expanded huntingtin fragments. A glutamineproline-rich domain, along with a charged domain, is critical for PQE-1 protein function. Analysis of pqe-1 suggests that proteins exist that specifically protect neurons from the toxic effects of expanded polyQ disease proteins.
Faber
Peter W
PW
Massachusetts General Hospital Cancer Center, 149-7202 13th Street, Charlestown, MA 02129, USA.
Voisine
Cindy
C
King
Daphne C
DC
Bates
Emily A
EA
Hart
Anne C
AC
D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics; D002874:Chromosome Mapping; D015801:Helminth Proteins / Q000235:genetics / Q000502:physiology*; D006816:Huntington Disease / Q000209:etiology*; D009474:Neurons / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D010455:Peptides / Q000235:genetics / Q000502:physiology* / Q000633:toxicity*; D055232:Proline-Rich Protein Domains; D014158:Transcription, Genetic
D015801:Helminth Proteins; D010455:Peptides; C097188:polyglutamine