HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?

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.

Figure 1

HDAC isoforms distribution in tissues and rat brain regions, as well as their subcellular localization. Am: Amigadala, As: Astrocytes, Ca/Pu: Caudate/Putamen, Co: Cortex, GP: Globus palidus, Hi: Hippocampus, LC: Locus coeruleus, Ne: neurons, Ol: oligodendrocytes, SNpc: Substantia nigra compacta, SNpr: Substantia nigra reticulata, VEC: Vessel endothelial cells; * classified from 1 (most expressed HDAC isoform) to 11 (less expressed HDAC isoform); ** diagrams are a graphical representation of the relative expression of each HDAC isoform in a scale from low to high (0–5), adapted from Broide et al. [11-13].

Figure 2

HDAC6 domain organization. Catalytic Domain I (CDI) primary sequence is highlighted in pale red; CDI three-dimensional structure obtained by homology modeling techniques by using HDAC7 x-ray structure as a template is represented with red ribbons. Catalytic Domain II (CDII) primary sequence is highlighted in pale green; CDII three-dimensional structure obtained by homology modeling techniques by using HDAC7 x-ray structure as a template is represented with green ribbons. Primary sequence of HDAC6 ubiquitin binding domain (ZnFUBP) is highlighted in blue whereas its three-dimensional structure (PDB ID 3C5K) is represented with cyan ribbons. Sequences corresponding to the tetradecapeptide repeating domain (SE14) and to the nuclear export domains NES1, NES2 are highlighted in pale gray, orange and yellow, respectively. Information about HDAC6 CD I/II and ZnFUBP secondary structures was retrieved from the human HDAC7 (PDB ID 3C10) and HDAC6 (PDB ID 3C5K) x-ray structures.

Figure 3

The role of HDAC6 in various processes related to neurodegeneration. I) The ubiquitin-proteasome system is impaired in many NDs resulting in the accumulation of highly ubiquitinated misfolded proteins tending to aggregate. II) HDAC6 binds to ubiquitinated protein aggregates (IIa) to constitute a novel organelle, the aggresome (IIb), where they are eventually eliminated by autophagy. III) The AAATPase p97/VCP is able to dissociate the complexes formed between HDAC6 and polyubiquitinated proteins to favor protein degradation. IV) Binding of HDAC6 to polyubiquitinated proteins triggers the dissociation of the HDAC6/HSP90/HSF1 complex, resulting in the activation of HSF1 (IVa). This induces gene expression of HSP70 and HSP27 (IVb), which exert a protective role against the toxic effects of the aggregates in cells. V) In AD neurons, HDAC6 interacts with tau and the excess of tau inhibits the deacetylase and ubiquitin ligase activities of HDAC6.