Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from huntingtin polyglutamine neurotoxicity

doi:10.1073/pnas.262544899

Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from huntingtin polyglutamine neurotoxicity

Massachusetts General Hospital Cancer Center, 149-7202 13th Street, Charlestown, MA 02129; and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115

Edited by H. Robert Horvitz, Massachusetts Institute of Technology, Cambridge, MA, and approved October 30, 2002 (received for review September 6, 2002)

Abstract

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 glutamine/proline-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.

Footnotes

↵ * P.W.F. and C.V. contributed equally to this work.
↵ † Present address: Exploratory Biology, Athersys Incorporated, Cleveland, OH 44115-2634.
↵ ‡ To whom correspondence should be addressed. E-mail: hart{at}helix.mgh.havard.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:
1. HD, Huntington's disease
2. polyQ, polyglutamine
3. DiD, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocynanine perchlorate