Roles of the MYST Family in the Pathogenesis of Alzheimer’s Disease via Histone or Non-histone Acetylation

Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.

Section: Elp3mentioning

confidence: 99%

The role of altered protein acetylation in neurodegenerative disease

Kabir

Atkinson

Cook

et al. 2023

“…P300 inhibitors can inhibit the expression of PSEN1 and bace1 by reducing H3 acetylation in the promoter region ( Lu et al, 2014 ; Kizuka et al, 2015 ). Some studies have shown that the acetylation of H2B and H4 in the hippocampus of rats can enhance the expression of memory-related genes, thereby enhancing their spatial memory ability ( Li Y. et al, 2021 ). Moreover, the acetyltransferase Tip60 induces gene transcription by forming a polymer in the cytoplasm with a ligand of APP and an intracellular subdomain of APP, which increases the acetylation of Tip60-dependent histone H3K14 and H4K5 ( Smith et al, 2021 ).…”

Section: Histone Modificationmentioning

confidence: 99%

Epigenetics in Alzheimer’s Disease

Gao

Chen

Yang

et al. 2022

Alzheimer’s disease (AD) is a neurodegenerative disease with unknown pathogenesis and complex pathological manifestations. At present, a large number of studies on targeted drugs for the typical pathological phenomenon of AD (Aβ) have ended in failure. Although there are some drugs on the market that indirectly act on AD, their efficacy is very low and the side effects are substantial, so there is an urgent need to develop a new strategy for the treatment of AD. An increasing number of studies have confirmed epigenetic changes in AD. Although it is not clear whether these epigenetic changes are the cause or result of AD, they provide a new avenue of treatment for medical researchers worldwide. This article summarizes various epigenetic changes in AD, including DNA methylation, histone modification and miRNA, and concludes that epigenetics has great potential as a new target for the treatment of AD.

“…A-type HATs are further divided into three subclasses based on their structural homology: (1) GNAT family represented by Gnc5, PCAF, and ELP3; (2) MYST family containing Tip60, MOZ/MYST3, MORF/MYST4, HBO1/MYST2, and HMOF/MYST1; and (3) p300/CBP family containing p300 and CBP. Multiple studies have been conducted to investigate the role of these HATS in the etiology of AD ( Lu et al, 2015 ; Li et al, 2021 ). HAT activity of Tip60 was shown to regulate the expression of genes that are related to behavior, learning, memory, and neuronal apoptosis in Drosophila ( Xu et al, 2014 ).…”

Section: Post-translational Modifications In Alzheimer’s Diseasementioning

confidence: 99%

Clinical relevance of biomarkers, new therapeutic approaches, and role of post-translational modifications in the pathogenesis of Alzheimer’s disease

Mumtaz

Ayaz

Khan

et al. 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes progressive loss of cognitive functions like thinking, memory, reasoning, behavioral abilities, and social skills thus affecting the ability of a person to perform normal daily functions independently. There is no definitive cure for this disease, and treatment options available for the management of the disease are not very effective as well. Based on histopathology, AD is characterized by the accumulation of insoluble deposits of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although several molecular events contribute to the formation of these insoluble deposits, the aberrant post-translational modifications (PTMs) of AD-related proteins (like APP, Aβ, tau, and BACE1) are also known to be involved in the onset and progression of this disease. However, early diagnosis of the disease as well as the development of effective therapeutic approaches is impeded by lack of proper clinical biomarkers. In this review, we summarized the current status and clinical relevance of biomarkers from cerebrospinal fluid (CSF), blood and extracellular vesicles involved in onset and progression of AD. Moreover, we highlight the effects of several PTMs on the AD-related proteins, and provide an insight how these modifications impact the structure and function of proteins leading to AD pathology. Finally, for disease-modifying therapeutics, novel approaches, and targets are discussed for the successful treatment and management of AD.