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.

Class I histone deacetylase inhibition by aryl butenoic acid derivatives: In silico and in vitro studies

“…Increased expression of HDAC 1 and HDAC 8 was reported in some cancer types such as myeloma and neuroblastoma [30,31]. Additionally, several reports indicated both neurotoxic or neuroprotective properties of HDAC 1 [8]. This is also the case for other HDACs, except HDAC 8, since there is lack of information about neurodegeneration.…”

“…Although HDACs are suitable as drug targets, this makes inhibitor design complicated and indicates that elucidating functions of HDAC subtypes are essential to evaluate the effects of inhibitors. Selective inhibitors can also be used as tools to understand functions of HDAC subtypes, as well [8]. Remaining HDAC activities (%)…”

“…In parallel to their functions, subcellular localization of class I HDACs is primarily nucleus, class II enzymes shuttle between nucleus and cytoplasm [6,7]. HDACs control multiple cellular processes such as proliferation, differentiation and apoptosis by either regulating İD İD İD İD İD gene expression directly or interacting with non-histone regulatory/structural proteins [8,9]. These properties make HDACs suitable targets for modifying molecular and cellular mechanisms.…”

“…Our group previously synthesized three aryl butenoic acid derivatives and identified their pan-HDAC inhibition activities [21,22]. In this study, we focused on class I HDACs (1,2,3,8) due to their catalytic potencies and analyzed selective inhibition activities of three aryl butenoic acid derivatives (C1, C3 and C4) by using in silico molecular modelling and in vitro activity screening approaches.…”

Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities

“…The complex relationship between the role of each isoform of HDAC and the displayed neuroprotective or neurotoxic effects is well known. 33 Some class I HDACs, for example, HDAC1, have been described as a molecular switch between neuronal death and survival, depending on their cooperative action with HDAC3 or HDAC-related protein, respectively. 34 On the other hand, HDAC3 activity has been associated with a high level of toxicity in neurons in a process that is dependent on its phosphorylation promoted by glycogen synthase kinase 3β (GSK3β).…”