HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration.
The two major intracellular catabolic pathways, the ubiquitin-proteasome system (UPS) and macroautophagy (autophagy), have each been implicated as playing roles in neurodegenerative proteinopathies. We have investigated the relationship between the UPS and autophagy using Drosophila models of neurodegenerative diseases. We identified histone deacetylase 6 (HDAC6) as a genetic modifier of polyglutamine-induced neurodegeneration and determined that its mechanism of action is autophagy-dependent. The ability of HDAC6 to suppress degeneration has been extended to additional neurodegenerative disease models, including a fly model expressing pathological Abeta fragments, presented here, but is not a universal modifier of degenerative phenotypes. Importantly, HDAC6 was also found to suppress degeneration associated with proteasome mutations in an autophagy-dependent manner, revealing a compensatory relationship between these two degradation pathways. Our findings indicate that HDAC6 facilitates degradation of potentially noxious protein substrates, contributing vitally to the neuroprotective role of autophagy.
Pandey
Udai Bhan
UB
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Batlevi
Yakup
Y
Baehrecke
Eric H
EH
Taylor
J Paul
JP
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; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D029721:Drosophila Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C425683:HDAC6 protein, Drosophila; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases