Complex neuroprotective and neurotoxic effects of histone deacetylases

Abstract

By their ability to shatter quality of life for both patients and caregivers, neurodegenerative diseases are the most devastating of human disorders. Unfortunately, there are no effective or long-terms treatments capable of slowing down the relentless loss of neurons in any of these diseases. One impediment is the lack of detailed knowledge of the molecular mechanisms underlying the processes of neurodegeneration. While some neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are mostly sporadic in nature, driven by both environment and genetic susceptibility, many others, including Huntington's disease, spinocerebellar ataxias, and spinal-bulbar muscular atrophy, are genetically inherited disorders. Surprisingly, given their different roots and etiologies, both sporadic and genetic neurodegenerative disorders have been linked to disease mechanisms involving histone deacetylase (HDAC) proteins, which consists of 18 family members with diverse functions. While most studies have implicated certain HDAC subtypes in promoting neurodegeneration, a substantial body of literature suggests that other HDAC proteins can preserve neuronal viability. Of particular interest, however, is the recent realization that a single HDAC subtype can have both neuroprotective and neurotoxic effects. Diverse mechanisms, beyond transcriptional regulation have been linked to these effects, including deacetylation of non-histone proteins, protein-protein interactions, post-translational modifications of the HDAC proteins themselves and direct interactions with disease proteins. The roles of these HDACs in both sporadic and genetic neurodegenerative diseases will be discussed in the current review.

Keywords: Huntington's disease; histone deacetylase; neurodegenerative diseases; neuroprotection.

Figure 1

Different mechanisms of actions for HDAC proteins. A. Traditional effects of HDAC to alter histone acetylation and chromatin structure leading to changes in gene transcription. B. HDACs can also deacetylate non-histone proteins including transcription factors, such as Nuclear factor-kappa beta (NF-KB), Mitogen-activated protein kinase phosphatase 1 (MKP-1) and Neural-restrictive silencer factor (NRSF), among others. C. Examples of interactions of class II HDACs with regulatory proteins, including Heterochromatin protein 1 (HP1) and C-terminal-binding protein (CTBP). Class II HDACs, such as HDAC4 and HDAC5, can also interaction with class I HDACs, such as HDAC3, as part of transcriptional regulatory complexes. The nuclear receptor co-repressor 2/ silencing mediator for retinoid and thyroid hormone receptors (N-Cor/SMRT) complex is shown as an example.