Class IIA HDACs in the regulation of neurodegeneration

Abstract

Neurodegenerative diseases affect millions of patients annually and are a significant burden on the health care systems around the world. While there are symptomatic remedies for patients suffering from various neurodegenerative diseases, there are no cures as of today. Cell death by apoptosis is a common hallmark of neurodegeneration. Therefore, deciphering the molecular pathways regulating this process is of significant value to scientists' endeavor to understand neurodegenerative disorders. Efforts along these lines have uncovered a number of molecular pathways that regulate neuronal apoptosis. Recently, a family of proteins known as histone deacetylases (HDACs) has been linked to regulation of cell survival as well as death. The focus of this review is to summarize our current understanding of the role of HDACs and in particular a subgroup of proteins in this family classified as class IIa HDACs in the regulation of neuronal cell death. It is apparent based on the information presented in this review that although very similar in their primary sequence, members of this family of proteins often have distinct roles in orchestrating apoptotic cell death in the brain.

Class IIa histone deacetylases: conducting development and differentiation

“…Indeed, a recent study reported that HDAC4 prevents low-potassium induced neuronal cell death, through inhibition of activity of cyclin-dependent kinase-1 (CDK1). Supporting their results, the authors described higher CDK1 activity in the brain of HDAC4-/-mice (Majdzadeh et al, 2008). Similarly, studies using a model of mouse retina degeneration showed that HDAC4 promotes survival of photoreceptor cells (Chen and Chepko, 2009).…”

“…In addition, HDAC5 knockdown mice showed no obvious brain defects, whereas mice lacking HDAC4 have abnormal shaped brains and exencephaly, probably resulting form precocious ossification of the brain (Vega et al, 2004b). However, more careful examination of HDAC4-null mice revealed delay in the formation of folia, suggesting a pro-survival rather than a pro-apoptotic role for HDAC4 (Majdzadeh et al, 2008;Vega et al, 2004b). Indeed, a recent study reported that HDAC4 prevents low-potassium induced neuronal cell death, through inhibition of activity of cyclin-dependent kinase-1 (CDK1).…”

“…More careful examination of class IIa HDAC null-mice should identify less obvious phenotypical defects and therefore suggest additional biological functions for these enzymes. For instance, while HDAC4-deficient mice die perinatally from skeletal defects, demonstrating the key role of this class IIa member in bone development, they also exhibit cerebellar abnormalities which could support a role for HDAC4 in neuronal survival (Majdzadeh et al, 2008). Surprisingly, and despite the fact that they can associate with a plethora of partners, the biological functions of class IIa HDACs seem to rely almost uniquely on their association with MEF2 transcription factors.…”

Dephosphorylation at a Conserved SP Motif Governs cAMP Sensitivity and Nuclear Localization of Class IIa Histone Deacetylases*

“…Among them are histone deacetylases 4, 5, 7, and 9 (HDAC4, -5, -7, and -9), 4 which are highly homologous and form a subgroup within class II. Cell-based studies have established that this group of enzymes plays important roles in skeletal muscle differentiation (5) and plasticity (6,7), cardiac hypertrophy (8), angiogenesis (9 -11), T-cell selection (12), and neurodegeneration (13). Not surprisingly, the knock-out mice display striking phenotypes; Hdac4 inactivation causes premature ossification of developing bones (14), Hdac4 Ϫ/Ϫ…”

Weighted Gene Co-Expression Network Analysis Identifies Specific Modules and Hub Genes Related to Hyperlipidemia

“…HDACs are divided into four classes (class I: HDAC1, 2, 3 and 8; class II: HDAC4, 5, 6, 7, 9 and 10; class III: SIRT1-7; class IV: HDAC11) [37]. HDAC4, one member of the tissuespecific Class II HDACs, is highly expressed in neurons [38] and bone mass, and plays an essential role in maintaining neuronal survival [39] and chondrocyte hypertrophy [40]. When we analysis the other 4 genes in UCSC, we could only find that the F2RL1 and ABHD2' concentrate peak appeared in H3K27AC before gene transaction, but nothing can (Fig.…”