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.
Little
is known about the biological and structural features that
govern the isoform selectivity for class I histone deacetylases (HDACs)
over HDAC6. In addition to that for known inhibitors, like benzamides,
psammaplin A, and cyclodepsipeptide-derived thiols, selectivity was
also observed for naturally occurring cyclopeptide HDAC inhibitors
with an aliphatic flexible linker and ketonelike zinc-binding group
(ZBG). The present study reports that this isoform selectivity is
mainly due to the linker and ZBG, as replacement of the cyclopeptide
cap region by a simple aniline retained class I HDAC isoform selectivity
toward HDAC6 in enzymatic assays. The best cyclopeptide-free analogues
preserved efficacy against Plasmodium falciparum and cancer cell lines. Molecular modeling provided hypotheses to
explain this selectivity and suggests different behaviors of the flexible
linker on HDAC1 and HDAC6 pockets, which may influence, on the basis
of the strength of the ZBG, its coordination with the zinc ion.
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