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Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders

Abstract

The expansion of a CAG repeat coding for polyglutamine in otherwise unrelated gene products is central to eight neurodegenerative disorders including Huntington's disease1. It has been well documented that expanded polyglutamine fragments, cleaved from their respective full-length proteins, form microscopically visible aggregates in affected individuals and in transgenic mice2,3,4,5,6,7. The contribution of polyglutamine oligomers to neurodegeneration, however, is controversial. The azo-dye Congo red binds preferentially to β-sheets containing amyloid fibrils8,9 and can specifically inhibit oligomerization10 and disrupt preformed oligomers. Here we show that inhibition of polyglutamine oligomerization by Congo red prevents ATP depletion and caspase activation, preserves normal cellular protein synthesis and degradation functions, and promotes the clearance of expanded polyglutamine repeats in vivo and in vitro. Infusion of Congo red into a transgenic mouse model of Huntington's disease, well after the onset of symptoms, promotes the clearance of expanded repeats in vivo and exerts marked protective effects on survival, weight loss and motor function. We conclude that oligomerization is a crucial determinant in the biochemical properties of expanded polyglutamine that are central to their chronic cytotoxicity.

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Figure 1: Effect of anti-amyloid compounds on cell death induced by polyglutamine.
Figure 2: Selective inhibition of polyglutamine oligomerization and cytotoxicity by Congo red.
Figure 3: FRET assay for polyglutamine oligomerization.
Figure 4: Inhibition of polyglutamine oligomerization prevents abnormal protein recruitment.
Figure 5: Effect of Congo red on polyglutamine turnover.
Figure 6: Effect of Congo red in the transgenic R62 mouse model of Huntington's disease.

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Acknowledgements

We thank E. Signer, S. Lokey, M. Kirschner, N. Ayad, M. Kobori, O.Gozani, L. Yoo, R. Sanchez-Olea, A. Degterev and R. King for comments; T. Mitchison for advice; M. Takeuchi for technical assistance; and X.-J. Li, A. Kazantsev and C. Cepko for reagents. This work was supported in part by grants from the Hereditary Disease Foundation and the NIH (to J.Y.).

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Correspondence to Junying Yuan.

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Sánchez, I., Mahlke, C. & Yuan, J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373–379 (2003). https://doi.org/10.1038/nature01301

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