HDAC6 in Diseases of Cognition and of Neurons

Abstract

Central nervous system (CNS) neurodegenerative diseases are characterized by faulty intracellular transport, cognition, and aggregate regulation. Traditionally, neuroprotection exerted by histone deacetylase (HDAC) inhibitors (HDACi) has been attributed to the ability of this drug class to promote histone acetylation. However, HDAC6 in the healthy CNS functions via distinct mechanisms, due largely to its cytoplasmic localization. Indeed, in healthy neurons, cytoplasmic HDAC6 regulates the acetylation of a variety of non-histone proteins that are linked to separate functions, i.e., intracellular transport, neurotransmitter release, and aggregate formation. These three HDAC6 activities could work independently or in synergy. Of particular interest, HDAC6 targets the synaptic protein Bruchpilot and neurotransmitter release. In pathological conditions, HDAC6 becomes abundant in the nucleus, with deleterious consequences for transcription regulation and synapses. Thus, HDAC6 plays a leading role in neuronal health or dysfunction. Here, we review recent findings and novel conclusions on the role of HDAC6 in neurodegeneration. Selective studies with pan-HDACi are also included. We propose that an early alteration of HDAC6 undermines synaptic transmission, while altering transport and aggregation, eventually leading to neurodegeneration.

LncRNA NORAD Promotes Vascular Endothelial Cell Injury and Atherosclerosis Through Suppressing VEGF Gene Transcription via Enhancing H3K9 Deacetylation by Recruiting HDAC6

“…Cytoplasmic lncRNA NORAD interacts with PUMILIO protein to regulate cell mitosis through regulating levels of PUMILIO-targeted mRNAs (Tichon et al, 2016). In addition, HDAC6 regulates the acetylation of numerous non-histone proteins in the cytoplasm (LoPresti, 2020). For instance, HDAC6-mediated deacetylation of Miro1 suppresses axon growth (Kalinski et al, 2019).…”

Borinostats: solid-phase synthesis of carborane-capped histone deacetylase inhibitors with a tailor-made selectivity profile

“…1,2,4 As overexpression of HDACs was shown to be linked with several cancer types, their selective inhibition results in several anticancer effects including terminal differentiation, growth arrest and apoptosis in cancer cells. 4,5,6,7 Therefore, HDAC inhibitors (HDACis) have emerged as valuable epigenetic modulators for treatment of cancer 6,7,8 as well as HIV, 9 inflammatory diseases, 10 immune disorders, neurodegenerative 11,12,13 and parasitic diseases. 15 There are eighteen human HDAC isoforms that have been divided into four classes according to their primary homology to yeast: Class I (HDACs 1, 2, 3 and 8), class IIa (HDACs 4, 5, 7, 9), class IIb (HDACs 6 and 10), class III (human sirtuins 1-7) and class IV (HDAC 11).…”

“…24 Within the HDAC family, HDAC6 has drawn major research attention due to occupying a very unique space in the therapeutic spectrum covering intracellular transport, neurotransmitter release, and aggresome formation. 13,16 Primarily localized in the cytoplasm it regulates the acetylation of α-tubulin, HSP90, 17,18 tau, cortactin, and amyloid β, and influences the microtubule formation and thereby the cell motility and metastatic potential. 19 Thus, several research groups have developed small molecule inhibitors with selectivity for this specific isoform mainly following a certain pharmacophore model (Figure 1).…”

How Influenza Virus Uses Host Cell Pathways during Uncoating

“…In humans, HDAC6 contains a Ser Glu-repeat domain (SE14), which acts as a cytoplasmic retention signal and mediates its stable anchorage in the cytoplasm [ 188 ] where it deacetylases tubulin [ 189 , 190 , 191 ], heat shock protein 90 (Hsp90) [ 192 , 193 , 194 ], β-catenin [ 195 , 196 ], cortactin [ 197 ], MYH9, Hsc70, DNAJA1 [ 198 ] or the DEAD box RNA helicase 3, X-linked (DDX3X) [ 199 ]. HDAC6 has been associated with carcinogenesis, neurodegenerative diseases and inflammatory disorders, and has been exploited as a therapeutic target for pharmacological intervention [ 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 ].…”