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.