Histone deacetylases or HDACs are associated with the removal of acetyl groups from histones and a host of other proteins. Class I, II and IV HDACs require Zn<sup>2+</sup> as a cofactor for their deacetylating activity and these are often referred to as the conventional HDACs. HDAC6 has garnished significant attention due to its unique structure and activity, and to the finding that HDAC6 knockout animals remain viable. While HDAC6 does not work on nuclear histones, it is involved in the acetylation status of proteins such as cortactin, HSF-1, HSP90, and tubulin. In particular, HDAC6 controls the acetylation status of the microtubule protein α-tubulin, and microtubule-dependent transport rates are more efficient along acetylated α-tubulin than deacetylated α-tubulin. This effect stems from the increased association of the motor proteins kinesin-1 and dynein with acetyl-tubulin, and therefore, affects both anterograde and retrograde transport activities. Thus, in addition to facilitating anterograde transport of new cargo to synaptic zones, acetyl-tubulin also increases the ability of damaged organelles or misfolded proteins to leave synaptic zones. This may be very important for Rett Syndrome, inter alia, as damaged mitochondria and elevated levels of improperly spliced mRNA transcripts have been noted in MeCP2-deficient neurons. In this lecture I will present information on the design, synthesis, and testing of ligands that are highly selective for HDAC6 inhibition and show the effects of these compounds in animal models of diseases such as Rett syndrome, Alzheimer’s disease, Charcot Marie Tooth disease, cancer, and stroke.

HDAC6 inhibitors, autophagy, mitochondrial movement, and disease modification

253rd National Meeting (2017)

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