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Human Molecular Genetics, 2002, Vol. 11, No. 23 2895-2904
© 2002 Oxford University Press

Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila

H.Y. Edwin Chan1,{dagger},{ddagger}, John M. Warrick1,{dagger},{ddagger}, Isabella Andriola2, Diane Merry2 and Nancy M. Bonini1,*

1Howard Hughes Medical Institute, Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA and 2Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, 208 Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, PA 19073, USA

Received July 3, 2002; Accepted August 16, 2002

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.

* To whom correspondence should be addressed. Email: nbonini{at}sas.upenn.edu

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be considered as joint First Authors.

{ddagger} Present addresses: H.Y.E. Chan, Department of Biochemistry, The Chinese University of Hong Kong, Shatin NT, Hong Kong. J.M. Warrick, Department of Biology, University of Richmond, Richmond, VA 23173, USA.


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