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HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS


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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Figure 1: HDAC6 rescues degeneration in flies with proteasome impairment and in a fly model of SBMA that exhibits impaired UPS function.
Figure 2: Induction of compensatory autophagy in flies with proteasome mutations and in SBMA flies.
Figure 3: HDAC6 accelerates the turnover of polyQ-expanded AR.
Figure 4: Rescue of degeneration by HDAC6 is autophagy-dependent.

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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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Correspondence to J. Paul Taylor.

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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).

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