Abstract
Histone deacetylase (HDAC) inhibitors have been demonstrated to be beneficial in animal models of neurodegenerative diseases. Such results were mainly associated with the epigenetic modulation caused by HDACs, especially those from class I, via chromatin deacetylation. However, other mechanisms may contribute to the neuroprotective effect of HDAC inhibitors, since each HDAC may present distinct specific functions within the neurodegenerative cascades. Such an example is HDAC6 for which the role in neurodegeneration has been partially elucidated so far. The strategy to be adopted in promising therapeutics targeting HDAC6 is still controversial. Specific inhibitors exert neuroprotection by increasing the acetylation levels of α-tubulin with subsequent improvement of the axonal transport, which is usually impaired in neurodegenerative disorders. On the other hand, an induction of HDAC6 would theoretically contribute to the degradation of protein aggregates which characterize various neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Hutington’s diseases. This review describes the specific role of HDAC6 compared to the other HDACs in the context of neurodegeneration, by collecting in silico, in vitro and in vivo results regarding the inhibition and/or knockdown of HDAC6 and other HDACs. Moreover, structure, function, subcellular localization, as well as the level of HDAC6 expression within brain regions are reviewed and compared to the other HDAC isoforms. In various neurodegenerative diseases, the mechanisms underlying HDAC6 interaction with other proteins seem to be a promising approach in understanding the modulation of HDAC6 activity.
Highlights
Histone deacetylases (HDACs) are enzymes that deacetylate lysine residues from histones as well as from several other nuclear, cytoplasmic and mitochondrial non-histone proteins
Class II is subdivided into classes IIa (HDAC4, 5, 7, and 9) and IIb (HDAC6 and 10)
The N-terminal domain found in class IIa members is the one responsible for nuclear-cytoplasmic shuttling through a phosphorylation-dependent binding to specific 14-3-3 proteins
Summary
Histone deacetylases (HDACs) are enzymes that deacetylate lysine residues from histones as well as from several other nuclear, cytoplasmic and mitochondrial non-histone proteins. HDACs 1 to 3 are found in complexes with specific transcriptional corepressors, blocking the expression of tumor suppressor genes [27] These enzymes share an internal dynamic cavity adjacent to the catalytic pocket that seems to facilitate the egress of the enzymatic products from the active site [20,22]. The N-terminal domain found in class IIa members is the one responsible for nuclear-cytoplasmic shuttling through a phosphorylation-dependent binding to specific 14-3-3 proteins. Such interactions regulate the activity of transcription factors such as the myocyte enhancer factor-2 (MEF2), which exerts a repressor role in a variety of biological functions, from myogenesis to Epstein-Barr virus transcriptional regulation [27]. What makes HDAC6 unique among all HDAC enzymes is the presence of the C-terminal zinc finger domain able to
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