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.
Autophagy. 2007 Nov-Dec;3(6):643-5. doi: 10.4161/auto.5050 Q114.62024
HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration
HDAC6在自噬、泛素-蛋白酶体系统和神经退行性疾病交叉点上的作用 翻译改进
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DOI: 10.4161/auto.5050 PMID: 17912024
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