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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Taylor, J. P., Hardy, J. & Fischbeck, K. H. Toxic proteins in neurodegenerative disease. Science 296, 1991–1995 (2002)
Trojanowski, J. Q. & Lee, V. M. “Fatal attractions” of proteins. A comprehensive hypothetical mechanism underlying Alzheimer’s disease and other neurodegenerative disorders. Ann. NY Acad. Sci. 924, 62–67 (2000)
Rubinsztein, D. C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780–786 (2006)
Ciechanover, A., Finley, D. & Varshavsky, A. Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell 37, 57–66 (1984)
Pickart, C. M. Back to the future with ubiquitin. Cell 116, 181–190 (2004)
Iwata, A., Riley, B. E., Johnston, J. A. & Kopito, R. R. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J. Biol. Chem. 280, 40282–40292 (2005)
Rideout, H. J., Lang-Rollin, I. & Stefanis, L. Involvement of macroautophagy in the dissolution of neuronal inclusions. Int. J. Biochem. Cell Biol. 36, 2551–2562 (2004)
Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006)
Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006)
Kawaguchi, Y. et al. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727–738 (2003)
Smyth, K. A. & Belote, J. M. The dominant temperature-sensitive lethal DTS7 of Drosophila melanogaster encodes an altered 20S proteasome β-type subunit. Genetics 151, 211–220 (1999)
Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993)
Ciechanover, A. & Brundin, P. The ubiquitin proteasome system in neurodegenerative diseases: Sometimes the chicken, sometimes the egg. Neuron 40, 427–446 (2003)
La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E. & Fischbeck, K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991)
Li, M. et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann. Neurol. 44, 249–254 (1998)
Takeyama, K. et al. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 35, 855–864 (2002)
Bence, N. F., Sampat, R. M. & Kopito, R. R. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1552–1555 (2001)
Neefjes, J. & Dantuma, N. P. Fluorescent probes for proteolysis: Tools for drug discovery. Nature Rev. Drug Discov. 3, 58–69 (2004)
Chan, H. Y., Warrick, J. M., Andriola, I., Merry, D. & Bonini, N. M. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum. Mol. Genet. 11, 2895–2904 (2002)
Taylor, J. P. et al. Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum. Mol. Genet. 12, 749–757 (2003)
McGuire, S. E., Mao, Z. & Davis, R. L. Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila. Sci. STKE 2004, pl6 (2004)
Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004)
Harris, T. E. & Lawrence, J. C. TOR signaling. Sci. STKE 2003, re15 (2003)
Kovacs, J. J. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601–607 (2005)
Taylor, J. P. et al. Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev. 17, 1463–1468 (2003)
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.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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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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