A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila

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Huntington disease is caused by the expansion of a polyglutamine repeat in the Huntingtin protein (Htt) that leads to degeneration of neurons in the central nervous system and the appearance of visible aggregates within neurons. We have developed and tested suppressor polypeptides that bind mutant Htt and interfere with the process of aggregation in cell culture. In a Drosophila model, the most potent suppressor inhibits both adult lethality and photoreceptor neuron degeneration. The appearance of aggregates in photoreceptor neurons correlates strongly with the occurrence of pathology, and expression of suppressor polypeptides delays and limits the appearance of aggregates and protects photoreceptor neurons. These results suggest that targeting the protein interactions leading to aggregate formation may be beneficial for the design and development of therapeutic agents for Huntington disease.

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Figure 1: Suppressor design and inhibition of aggregation in cell culture.
Figure 2: A bivalent suppressor is required for inhibition of aggregation.
Figure 3: Suppressors decrease aggregation and co-localize with expanded polyQ proteins.
Figure 4: Expression of suppressor rescues lethality in Drosophila.
Figure 5: Expression of suppressor rescues neurodegeneration of photoreceptors.
Figure 6: Suppressor peptide suppresses and delays polyQ aggregate formation in the central nervous system.
Figure 7: Aggregation in the developing Drosophila eye imaginal disc is delayed and inhibited by suppressor peptide.

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The authors wish to thank J. Pallos, L. Bodai, E. Signer, N. Wexler and A. Tobin for many helpful discussions and E. Wanker for GST-Htt fusion proteins. The Elav hybridoma antibody developed by G.M. Rubin was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biological Sciences, Iowa City. This work was supported by a Cure Huntington's Disease Initiative grant from the Hereditary Disease Foundation (to L.M.T. and J.L.M.), the Lieberman Award from the Hereditary Disease Foundation (to L.M.T.), the Human Frontiers Science program (to L.M.T.), a Special Fellow Award from Leukemia and Lymphoma Society (to J.E.B.), a grant from the Sierra Foundation (to D.E.H.), and awards from the National Institutes of Health (to J.L.M., F.B.G. and D.E.H.). This work was made possible in part through access to the Optical Biology Shared Resource of the Cancer Center Support Grant at the University of California, Irvine and the National Drosophila Stock Center in Bloomington, Indiana.

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Correspondence to Leslie M. Thompson.

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