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.
Highlights
Histone deacetylases (HDACs) play a central role in the epigenetic regulation of Central nervous system (CNS) function, with emphasis on development, neurodegenerative diseases, and various mental disorders [1,2,3]
Pharmacophore models for new inhibitors of HDAC6 focus on a zinc-binding group (ZBG), a linker, and a cap
Cognition and higher brain functions rely on precise protein–protein regulation at the synapses, which allows information among neurons to travel along functionally distinct regions of the CNS
Summary
Histone deacetylases (HDACs) play a central role in the epigenetic regulation of CNS function, with emphasis on development, neurodegenerative diseases, and various mental disorders [1,2,3]. Eleven HDACs are zinc-dependent isoforms, including class I (HDACs 1/2/3/8), II (HDACs 4/5/6/7/9/10), and IV (HDAC 11). Histone substrates and class I HDAC isoforms are considered central to memory regulation. HDAC6, a member of class IIb, localizes largely in the cytoplasm and is the only HDAC isoform with two tandem catalytic domains [8,9]. HDAC6 inhibitors (HDAC6i) facilitate the degradation of protein aggregates and/or protection from neuronal oxidative stress (Figure 2) [9,10,11,12]. The zinc-binding residues in the catalytic domains of HDAC6 have been a target for the discovery of HDAC6i. Pharmacophore models for new inhibitors of HDAC6 focus on a zinc-binding group (ZBG), a linker, and a cap. Sitescellular of regulation are indicated the level processes, and soma
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