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.

Keywords: aggregates; cognition; intracellular transport; neurodegeneration; progressive multiple sclerosis; synapses.

Figure 1

Domains and functions of HDAC6. HDAC6 is the largest protein of the HDAC family, with 1215 amino acid residues. ZnF-UB (zinc-finger ubiquitin binding) is a high-affinity ubiquitin-binding motif, and DAC (deacetylase) (1 and 2) is the domain with deacetylase activity. Targets for DAC1 and DAC2 are based on work largely done in Drosophila [13]. Additional targets include survivin, β-catenin, peroxiredoxin, and Miro1. NES = nuclear export sequences, DMB = dynein motor binding, SE14 = Ser-Glu tetradecapeptide repeating domain [9]. NES1 (Aa: 67–76), DAC1 (Aa: 87–447), DAC2 (Aa: 482–800), SE14 (Aa: 884–1022), NES2 (Aa: 1049–1058), ZnF-UB (Aa: 1131–1192) [9].

Figure 2

Cellular sites of HDAC6 inhibitors in neurodegenerative diseases. HDAC6 inhibitors (HDAC6i) regulate a variety of events including growth cone function, synaptic plasticity, transport, and autophagosomal degradation. The intracellular sites of regulation are indicated at the level of growth cone, processes, and soma.

Figure 3

HDAC6 inhibitors in neurodegenerative diseases. HDAC6 inhibitors (HDAC6i) have been studied in several diseases (e.g., degenerative, developmental, and following toxins/infection) and have been shown to improve a combination of pathologies including inflammation, cell damage, transport regulation, aggregation, cognition, and disease course. The results shown in this figure reflect studies done with the drugs as indicated. As additional HDAC6i are developed and more studies are performed, additional results could add insight into the overall benefits of this class of drugs. All the drugs indicated are HDAC6i with the exception of Trichostatin A, an inhibitor for class I and II HDAC isoforms.