Hum Mol Genet. 2002 Nov 1;11(23):2895-904.

Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila.

Chan HY, Warrick JM, Andriola I, Merry D, Bonini NM.

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Howard Hughes Medical Institute, Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a heritable neurodegenerative disease caused by the expansion of a polyglutamine [poly(Q)] repeat within the androgen receptor (AR) protein. We studied SBMA in Drosophila using an N-terminal fragment of the human AR protein. Expression of a pathogenic AR protein with an expanded poly(Q) repeat in Drosophila results in nuclear and cytoplasmic inclusion formation, and cellular degeneration, preferentially in neuronal tissues. We have studied the influence of ubiquitin-dependent modification and the proteasome pathway on neural degeneration and AR protein fragment solubility. Compromising the ubiquitin/proteasome pathway enhances degeneration and decreases poly(Q) protein solubility. Our data further suggest that Hsp70 and the proteasome act in an additive manner to modulate neurodegeneration. Through the over-expression of a mutant of the SUMO-1 activating enzyme Uba2, we further show that poly(Q)-induced degeneration is intensified when the cellular SUMO-1 protein conjugation pathway is altered. These data suggest that post-translational protein modification, including the ubiquitin/proteasome and the SUMO-1 pathways, modulate poly(Q) pathogenesis.

PMID:: 12393801; [PubMed - indexed for MEDLINE]

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[Triplet repeat disease, with particular emphasis of spinal and bulbar muscular atrophy (SBMA)]. [Rinsho Shinkeigaku. 2000]
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