HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS (original) (raw)

Nature volume 447, pages 860–864 (2007)Cite this article

Abstract

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons1. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration2. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway3. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection4,5. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology6,7,8,9. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins10, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.

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Acknowledgements

We thank the Laboratory for Biological Ultrastructure at the University of Maryland for assistance with SEM, the Biomedical Imaging Core at the University of Pennsylvania for assistance with TEM, J. Belote and K. Takeyama for flies, and R. Kopito for the CL1–GFP construct. Financial support was provided by NIH grants to T.-P.Y., E.H.B. and J.P.T., as well as support from the Morton Reich Research Fund, Kennedy’s Disease Association, and Muscular Dystrophy Association to J.P.T.

Author Contributions Experimental work was performed by U.B.P., Z.N., Y.B., B.A.M., G.P.R., S.L.S., D.L.B. and J.P.T. Vital reagents were provided by N.A.D., M.A.K., O.S., R.P., M.H., D.G. and T.-P.Y. The manuscript was written by N.B.N., E.H.B. and J.P.T. All authors discussed results and commented on the manuscript.

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Authors and Affiliations

  1. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA,
    Udai Bhan Pandey, Zhiping Nie, Brett A. McCray, Gillian P. Ritson, Natalia B. Nedelsky, Stephanie L. Schwartz & J. Paul Taylor
  2. Center for Biosystems Research, University of Maryland Biotechnology Institute, College Park, Maryland 20742, USA,
    Yakup Batlevi, Deborah L. Berry & Eric H. Baehrecke
  3. Neurogenetics Branch, NINDS, NIH, Bethesda, Maryland 20817, USA,
    Nicholas A. DiProspero & Melanie A. Knight
  4. Department of Biological Sciences, Stanford University, Stanford, California 94305, USA,
    Oren Schuldiner
  5. Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA,
    Ranjani Padmanabhan, Marc Hild & Dan Garza
  6. Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA,
    Charlotte C. Hubbert & Tso-Pang Yao

Authors

  1. Udai Bhan Pandey
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  2. Zhiping Nie
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  3. Yakup Batlevi
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  4. Brett A. McCray
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  5. Gillian P. Ritson
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  6. Natalia B. Nedelsky
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  7. Stephanie L. Schwartz
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  8. Nicholas A. DiProspero
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  9. Melanie A. Knight
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  10. Oren Schuldiner
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  11. Ranjani Padmanabhan
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  12. Marc Hild
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  13. Deborah L. Berry
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  14. Dan Garza
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  15. Charlotte C. Hubbert
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  16. Tso-Pang Yao
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  17. Eric H. Baehrecke
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  18. J. Paul Taylor
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Correspondence toJ. Paul Taylor.

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Supplementary Information 1

This file contains Supplementary Figures and Legends S1-S12, Supplementary Methods, and additional references. (PDF 2122 kb)

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Pandey, U., Nie, Z., Batlevi, Y. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS.Nature 447, 860–864 (2007). https://doi.org/10.1038/nature05853

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Editorial Summary

Autophagy to the rescue

There are two main pathways that rid a cell of the protein misfits accumulated with time, the ubiquitin-proteasome system and autophagy, the self-destruction of a cell's own components through its lysosomal machinery. Work on a Drosophila model of neurodegenerative disease, in which the ubiquitin proteasome system breaks down, shows that autophagy can compensate for this loss. The two protein-destroying pathways are linked in vivo, with the microtubule-associated-histone deacetlyase HDAC6 acting as the link. Expression of HDAC6 is sufficient to induce autophagy and rescue neurodegeneration in the flies. These findings illuminate the relationship between autophagy and the ubiquitin-proteasome system, with implications for the pathogenesis and possible treatment of neurodegenerative proteopathies.