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A toxic mutant huntingtin species is resistant to selective autophagy

Nature Chemical Biology volume 13, pages 1152–1154 (2017)Cite this article

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Abstract

Protein misfolding is a common theme in neurodegenerative disorders including Huntington's disease (HD). The HD-causing mutant huntingtin protein (mHTT) has an expanded polyglutamine (polyQ) stretch that may adopt multiple conformations, and the most toxic of these is the one recognized by antibody 3B5H10. Here we show that the 3B5H10-recognized mHTT species has a slower degradation rate due to its resistance to selective autophagy in human cells and brains, revealing mechanisms of its higher toxicity.

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Figure 1: The 3B5H10-recognized mHTT species has slower degradation.
Figure 2: The difference in degradation between the 3B5H10-recognized and the MW1-recognized species is due to selective autophagy.
Figure 3: The 3B5H10-recognized mHTT species lacks K63 polyubiquitination and p62 recognition.

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Acknowledgements

The authors wish to thank C. Lu (biostatistician) for the statistical analysis, L. Ma and S. Hexige at Fudan University for sharing some of the patient fibroblast lines, K. Kegel at MGH Harvard Medical School for cDNA plasmids, E. Sapp at MGH Harvard Medical School for lysate of the human post-mortem brain tissues, and the National Natural Science Foundation of China (31422024, 91649105, 31371421, 31601105) and the National Key Research and Development Program of China (2016YFC0905100) for funding.

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Author notes

  1. Yuhua Fu, Peng Wu, Yuyin Pan and Xiaoli Sun: These authors contributed equally to this work.

Authors and Affiliations

  1. Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology, School of Life Sciences, Fudan University, Shanghai, China

    Yuhua Fu, Peng Wu, Yuyin Pan, Xiaoli Sun, Huiya Yang & Boxun Lu

  2. Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Xiaoli Sun

  3. MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Boston, USA

    Marian Difiglia

  4. Collaborative Innovation Center of Genetics and Development, Shanghai, China

    Boxun Lu

Authors
  1. Yuhua Fu
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  7. Boxun Lu
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Contributions

B.L. perceived the idea, initiated the project and designed the experiments. P.W., Y.F., Y.P. and X.S. performed the CH-chase experiments. Y.F. performed all the immunoprecipitation–western experiments with the help from others for blinding. H.Y. did the cell culture, molecular cloning and protein extraction. M.D. provided essential reagents and intellectual inputs.

Corresponding author

Correspondence to Boxun Lu.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–10 (PDF 5350 kb)

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Fu, Y., Wu, P., Pan, Y. et al. A toxic mutant huntingtin species is resistant to selective autophagy. Nat Chem Biol 13, 1152–1154 (2017). https://doi.org/10.1038/nchembio.2461

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