The expression of the newly discovered Poly-Q Enhancer (PQE) gene protects a worm against Huntington's disease. We can expect PQE genes to be found in humans. This will open new paths to the treatment of HD. --Jerry

Posted to HDLighthouse: 18 Dec 2002 HDL Update: Gene Protects Against Huntington's Disease

Worm Aids HD Discovery "We are using genetic, molecular, cellular and behavioral approaches in C. elegans to study the nervous system. The nematode C. elegans is uniquely suited for this analysis -- the nervous system consists of only 302 neurons whose location and synaptic connections are all known. Yet, this small nervous system is remarkably similar to vertebrate nervous sytems." Anne C. Hart, Assistant Professor, Harvard Medical School and study author.

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.

Source: Proc Natl Acad Sci U S A 2002 Dec 16;

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