HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements

Abstract

For the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III, and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure, and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes.

Keywords: HDAC inhibitors; HDAC4; histone deacetylase; neurodegeneration; signaling; therapeutic potential.

Figure 1

Structure and cellular function of HDAC4. (A) Summary of HDAC4 post translational modifications. CC, coil-coil domain; TBD, transcription binding domain; NLS, nuclear localisation signal; NES, nuclear export signal; DAC, deacetylation domain. (B) Summary underlying HDAC4 cellular localization and identified functions spanning all tested systems. HDAC4 undergoes nuclear-cytoplasmic shuttling in response to different stimuli through multiple kinases (1). In the cytoplasm, HDAC4 might be cleaved by proteases (2) to generate a small N-terminal fragment that translocates into the nuclei (3) to bind different transcription factors (TF) and repress their driven transcription. Similarly the full length HDAC4 upon dephosphorylation by phosphatases (4) translocates into the nuclei to act as a repressor of TF. In the nuclei, HDAC4 is cleaved by unknown protease to produce a distinct nuclear N-terminal fragment (5). Treatment with HDACIs might lead to the RANBP2-mediated proteasome degradation of HDAC4 (6). HDAC4 as a non-active deacetylase can also bind HDAC3 (7) to enhance its deacetylase activity (8). HDAC4 as a scaffolding protein prompts to form many complexes and has showed a cytosolic pro-aggregation propensity in HD mouse models (9).

Figure 2

A general mechanism of HDACIs (HDAC Inhibitors) action. Class I (HDACs: 1, 2, 3, 8), Class IIa (HDACs: 4, 5, 7, 9), Class IIb (HDACs: 6, 10), Class III (sirtuins 1-7), and Class IV (HDAC11).