NAD ⁺ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(8)

Published: Feb. 5, 2018

Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer's disease (AD), but their role in disease-defining pathology is unclear. We developed a repair-deficient 3xTgAD/Polβ

Language: Английский

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SIRT6, a Mammalian Deacylase with Multitasking Abilities

Physiological Reviews, Journal Year: 2019, Volume and Issue: 100(1), P. 145 - 169

Published: Aug. 22, 2019

Mammalian sirtuins have emerged in recent years as critical modulators of multiple biological processes, regulating cellular metabolism, DNA repair, gene expression, and mitochondrial biology. As such, they evolved to play key roles organismal homeostasis, defects these proteins been linked a plethora diseases, including cancer, neurodegeneration, aging. In this review, we describe the SIRT6, chromatin deacylase with unique important functions maintaining homeostasis. We attempt provide framework for such different functions, ability SIRT6 interconnect dynamics metabolism open questions field will face future, particularly context putative therapeutic opportunities.

Language: Английский

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Understanding the Role of Histone Deacetylase and their Inhibitors in Neurodegenerative Disorders: Current Targets and Future Perspective

Current Neuropharmacology, Journal Year: 2021, Volume and Issue: 20(1), P. 158 - 178

Published: June 21, 2021

Neurodegenerative diseases are a group of pathological conditions that cause motor incordination (jerking movements), cognitive and memory impairments result from degeneration neurons in specific area the brain. Oxidative stress, mitochondrial dysfunction, excitotoxicity, neuroinflammation, neurochemical imbalance histone deacetylase enzymes (HDAC) known to play crucial role neurodegeneration. HDAC is classified into four categories (class I, II, III class IV) depending upon their location functions. HDAC1 2 involved neurodegeneration, while HDAC3-11 HDACs beneficial as neuroprotective. localized different parts brain- (hippocampus cortex), HDAC2 (nucleus), HDAC3, 4, 5, 7 9 (nucleus cytoplasm), HDAC6 & HDAC7 (cytoplasm) HDAC11 (Nucleus, cornus ammonis 1 spinal cord). In conditions, up-regulates glutamate, phosphorylation tau, glial fibrillary acidic proteins down-regulating BDNF, Heat shock protein 70 Gelsolin. Class divided seven sub-classes (SIRT1-SIRT7). Sirtuins brain neuron -Sirt1 Sirt2 (cortex, striatum, hippocampus cord), Sirt3 (mitochondria Sirt4, Sirt5 Sirt6 (mitochondria), Sirt7 (nucleus) Sirt8 (nucleolus). SIRTs (1, 3, 6) neuronal survival, proliferation modulating stress response, SIRT2 associated with Parkinsonism, Huntington's disease Alzheimer's disease, whereas SIRT6 only disease. this critical review, we have discussed mechanisms therapeutic targets would be for management neurodegenerative disorders.

Language: Английский

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SIRT1 and SIRT6: The role in aging-related diseases

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2023, Volume and Issue: 1869(7), P. 166815 - 166815

Published: July 26, 2023

Aging is characterized by progressive functional deterioration with increased risk of mortality. It a complex biological process driven multitude intertwined mechanisms such as DNA damage, chronic inflammation, and metabolic dysfunction. Sirtuins (SIRTs) are family NAD+-dependent enzymes that regulate fundamental functions from genomic stability lifespan to energy metabolism tumorigenesis. Of the seven mammalian SIRT isotypes (SIRT1-7), SIRT1 SIRT6 well-recognized for regulating signaling pathways related aging. Herein, we review protective role in aging-related diseases at molecular, cellular, tissue, whole-organism levels. We also discuss therapeutic potential modulators treatment these challenges thereof.

Language: Английский

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SIRT6 is a key regulator of mitochondrial function in the brain

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 18, 2023

Abstract The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it critical roles the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics metabolomics approaches characterize functions of mouse brains. Our analysis reveals that is a central regulator mitochondrial activity brain. deficiency leads with global downregulation mitochondria-related genes pronounced changes metabolite content. We suggest affects through interaction transcription factor YY1 that, together, regulate gene expression. Moreover, target include SIRT3 SIRT4, which are significantly downregulated SIRT6-deficient results demonstrate lack decreased expression metabolomic TCA cycle byproducts, including increased ROS production, reduced number, impaired membrane potential can be partially rescued by restoring SIRT4 levels. Importantly, observed brains also occurring aging human particularly patients Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic lateral sclerosis disease. Overall, our levels neurodegeneration initiate dysfunction altering expression, decay.

Language: Английский

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SIRT6 is a DNA double-strand break sensor

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Jan. 29, 2020

DNA double-strand breaks (DSB) are the most deleterious type of damage. In this work, we show that SIRT6 directly recognizes damage through a tunnel-like structure has high affinity for DSB. relocates to sites independently signaling and known sensors. It activates downstream DSB repair by triggering ATM recruitment, H2AX phosphorylation recruitment proteins homologous recombination non-homologous end joining pathways. Our findings indicate plays previously uncharacterized role as sensor, critical factor in initiating response (DDR). Moreover, other Sirtuins share some DSB-binding capacity DDR activation. before pathway is chosen, prevents genomic instability. place sensor DSB, pave road dissecting contributions distinct sensors signaling.

Language: Английский

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Emerging roles of SIRT6 in human diseases and its modulators

Medicinal Research Reviews, Journal Year: 2020, Volume and Issue: 41(2), P. 1089 - 1137

Published: Dec. 16, 2020

Abstract The biological functions of sirtuin 6 (SIRT6; e.g., deacetylation, defatty‐acylation, and mono‐ADP‐ribosylation) play a pivotal role in regulating lifespan several fundamental processes controlling aging such as DNA repair, gene expression, telomeric maintenance. Over the past decades, aberration SIRT6 has been extensively observed diverse life‐threatening human diseases. In this comprehensive review, we summarize critical roles onset progression diseases including cancer, inflammation, diabetes, steatohepatitis, arthritis, cardiovascular diseases, neurodegenerative viral infections, renal corneal injuries, well elucidation related signaling pathways. Moreover, discuss advances development small molecule modulators activators inhibitors their pharmacological profiles toward potential therapeutics for SIRT6‐mediated

Language: Английский

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Sirtuins in Neuroendocrine Regulation and Neurological Diseases

Frontiers in Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: Oct. 26, 2018

Silent information regulator 1 (SIRT1) is a mammalian homolog of the nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase sirtuin family. Sirtuin was originally studied as lifespan-extending gene, silent 2 (Sir2) in budding yeast. There are seven homologues (SIRT1–7), and SIRT1 closest to Sir2. modulates various key targets via deacetylation. In addition histones, these include transcription factors, such forkhead box O (FOXO), Ku70, p53, NF-κB, PPAR-gamma co-activator 1-alpha (PGC-1α), peroxisome proliferator-activated receptor γ (PPARγ). has many biological functions, including aging, cell survival, differentiation, metabolism. Genetic physiological analysis animal models shown beneficial roles for brain during both development adulthood. Evidence from vivo vitro studies have revealed that regulates cellular fate neural progenitors, axon elongation, dendritic branching, synaptic plasticity, endocrine function. its importance processes, also been implicated protection neurons degeneration neurological diseases traumatic injury Alzheimer's disease. this review, we focus on role neuroendocrine system neurodegenerative diseases. We discuss potential therapeutic implications targeting pathway.

Language: Английский

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Protein acetylation and deacetylation: An important regulatory modification in gene transcription (Review)

Experimental and Therapeutic Medicine, Journal Year: 2020, Volume and Issue: unknown

Published: July 29, 2020

Cells primarily rely on proteins to perform the majority of their physiological functions, and function is regulated by post‑translational modifications (PTMs). The acetylation a dynamic highly specific PTM, which has an important influence functions proteins, such as gene transcription signal transduction. dependent lysine acetyltransferases deacetylases. In recent years, due widespread use mass spectrometry emergence new technologies, protein chips, studies have been further developed. Compared with histone acetylation, non‑histone gradually become focus research its regulatory mechanisms wide range applications. discovery sites using bioinformatic tools can greatly aid understanding underlying involved in related pathological processes.

Language: Английский

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A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD⁺-Dependent Enzymes

Journal of the American Chemical Society, Journal Year: 2019, Volume and Issue: 141(13), P. 5169 - 5181

Published: March 11, 2019

DNA-encoded chemical libraries are increasingly used in pharmaceutical research because they enable the rapid discovery of synthetic protein ligands. Here we explored whether target-class focused can be cost-effective tools to achieve robust screening productivity for a series proteins. The study revealed that library designed NAD+-binding pockets (NADEL) effectively sampled binder space enzymes with ADP-ribosyltransferase activity. extracted information directed synthesis inhibitors several including PARP15 and SIRT6. high dissimilarity NADEL fingerprints different proteins translated into showed selectivity their target. patterns enriched structures six out eight tested is remarkable 58 302 DNA-tagged illustrates prospect as economic alternatives large platforms.

Language: Английский

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