title: HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS.
abstract: A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. 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 pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. 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 pathology. 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 proteins, 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.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Udai Bhan
authors.initials: UB
authors.lastname: Pandey
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Nie
authors.forename: Yakup
authors.initials: Y
authors.lastname: Batlevi
authors.forename: Brett A
authors.initials: BA
authors.lastname: McCray
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Ritson
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Nedelsky
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Schwartz
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: DiProspero
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Knight
authors.forename: Oren
authors.initials: O
authors.lastname: Schuldiner
authors.forename: Ranjani
authors.initials: R
authors.lastname: Padmanabhan
authors.forename: Marc
authors.initials: M
authors.lastname: Hild
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Berry
authors.forename: Dan
authors.initials: D
authors.lastname: Garza
authors.forename: Charlotte C
authors.initials: CC
authors.lastname: Hubbert
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.forename: Eric H
authors.initials: EH
authors.lastname: Baehrecke
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020966:Muscular Disorders, Atrophic / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D010455:Peptides; D011944:Receptors, Androgen; D025801:Ubiquitin; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex; C425683:HDAC6 protein, Drosophila; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases