The NDR family of kinases: essential regulators of aging DOI Creative Commons

Kevin Jonischkies,

Miguel del Ángel, Yunus Emre Demiray

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: May 13, 2024

Aging is defined as a progressive decline of cognitive and physiological functions over lifetime. Since the definition nine hallmarks aging in 2013 by López-Otin, numerous studies have attempted to identify main regulators contributors process. One interesting group proteins whose participation has been implicated several are nuclear DBF2-related (NDR) family serine-threonine AGC kinases. They one core components Hippo signaling pathway include NDR1, NDR2, LATS1 LATS2 mammals, along with its highly conserved metazoan orthologs; Trc Drosophila melanogaster , SAX-1 Caenorhabditis elegans CBK1, DBF20 Saccharomyces cerevisiae orb6 pombe . These kinases independently linked regulation widely diverse cellular processes disrupted during such cell cycle progression, transcription, intercellular communication, nutrient homeostasis, autophagy, apoptosis, stem differentiation. However, comprehensive overview state-of-the-art knowledge regarding post-translational modifications NDR not conducted. In this review, we summarize current understanding kinases, focusing on their relevance various hallmarks, emphasize growing body evidence that suggests essential across species.

Language: Английский

Senescence: A DNA damage response and its role in aging and Neurodegenerative Diseases DOI Creative Commons

Tejal Shreeya,

Mohd. Saifullah Ansari,

Prabhat Kumar

et al.

Frontiers in Aging, Journal Year: 2024, Volume and Issue: 4

Published: March 21, 2024

Senescence is a complicated, multi-factorial, irreversible cell cycle halt that has tumor-suppressing effect in addition to being significant factor aging and neurological diseases. Damaged DNA, neuroinflammation, oxidative stress disrupted proteostasis are few of the factors cause senescence. triggered by DNA damage which initiates response. The response, includes formation foci containing activated H2AX, key cellular senescence, provoked double strand break. Oxidative impairs cognition, inhibits neurogenesis, an accelerated effect. Senescent cells generate pro-inflammatory mediators known as senescence-associated secretory phenotype (SASP). These cytokines chemokines have impact on neuronal death, proliferation. While it tempting think neurodegenerative diseases manifestations this review will present information brain ageing neurodegeneration result senescence

Language: Английский

Citations

14
Alpha-synuclein pathology is associated with astrocyte senescence in a midbrain organoid model of familial Parkinson's disease DOI Creative Commons

Mudiwa Nathasia Muwanigwa,

Jennifer Modamio-Chamarro,

Paul Antony

et al.

Molecular and Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 128, P. 103919 - 103919

Published: Feb. 1, 2024

Parkinson's disease (PD) is a complex, progressive neurodegenerative characterized by the loss of dopaminergic neurons in substantia nigra pars compacta midbrain. Despite extensive research efforts, molecular and cellular changes that precede neurodegeneration PD are poorly understood. To address this, here we describe use patient specific human midbrain organoids harboring SNCA triplication to investigate mechanisms underlying degeneration. Our organoid model recapitulates key pathological hallmarks PD, including aggregation α-synuclein neurons. We found these associated with an increase senescence phenotypes astrocytes nuclear lamina defects, presence heterochromatin foci, upregulation cell cycle arrest genes. These results suggest role inducing astrosenescence which may, turn, vulnerability

Language: Английский

Citations

11
Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway DOI Creative Commons

Ji-Ji Dao,

Wei Zhang, Chong Liu

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 31, 2025

Neuronal senescence is a common pathological feature of various neurodegenerative diseases, with ferroptosis playing significant role. This study aims to investigate the role ErbB4 receptor activation in preventing D-Galactose (D-gal)-induced neuronal senescence. Mice subjected D-gal-induced aging were administered small molecule agonist (E4A), identified via virtual screening, melatonin, or combination both. Behavioral assessments conducted evaluate therapeutic efficacy memory and cognitive functions. Immunofluorescence staining, western blot, biochemical assays primarily employed assess changes both senescence- ferroptosis-related molecules mouse hippocampal tissues response each treatment. Additionally, HT22 cell cultures utilized corroborate vivo findings. The targeted by E4A significantly ameliorated behavioral deficits induced D-gal mice, demonstrating an effect comparable that natural inhibitor ferroptosis. Both melatonin mitigated neurons mice. was evidenced upregulation Lamin B1 downregulation P53, P21, P16, GFAP, Iba-1 expression levels. Moreover, treatment markedly decreased protein Nrf2 while augmenting promoter TFRC. These alterations partially reversed individual administration melatonin. In vitro studies further corroborated concurrently markers promoters. However, able reverse these changes. Erastin-induced cells. Our findings suggest may be viable strategy for treating inhibiting ferroptosis, thereby offering potential avenue senescence-associated diseases.

Language: Английский

Citations

1
The senolytic ABT-263 improves cognitive functions in middle-aged male, but not female, atherosclerotic LDLr−/−;hApoB100+/+ mice DOI Creative Commons
Mélanie Lambert,

Géraldine Miquel,

Louis Villeneuve

et al.

GeroScience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Language: Английский

Citations

1
Drainage of senescent astrocytes from brain via meningeal lymphatic routes DOI
Qian Li, Yan Chen, Weixi Feng

et al.

Brain Behavior and Immunity, Journal Year: 2022, Volume and Issue: 103, P. 85 - 96

Published: April 12, 2022

Language: Английский

Citations

32
Reactive and Senescent Astroglial Phenotypes as Hallmarks of Brain Pathologies DOI Open Access
Andrijana Lazic, Vanda Balint, Danijela Stanisavljević Ninković

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(9), P. 4995 - 4995

Published: April 30, 2022

Astrocytes, as the most abundant glial cells in central nervous system, are tightly integrated into neural networks and participate numerous aspects of brain physiology pathology. They main homeostatic loss astrocyte physiological functions and/or gain pro-inflammatory functions, due to their reactivation or cellular senescence, can have profound impacts on surrounding microenvironment with pathological outcomes. Although importance astrocytes is generally recognized, both senescence reactive astrogliosis been extensively reviewed independently, there only a few comparative overviews these complex processes. In this review, we summarize latest data regarding outline similarities differences between phenotypes from morphological, functional, molecular points view. A special focus has given neurodegenerative diseases, where phenotypic alternations significantly implicated. We also current perspectives new advances model systems based well pointing potential therapeutic targets.

Language: Английский

Citations

32
Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity DOI
Vilija Jokubaitis, Maria Pia Campagna, Omar Ibrahim

et al.

Brain, Journal Year: 2022, Volume and Issue: 146(6), P. 2316 - 2331

Published: Nov. 28, 2022

Abstract Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity multiple clinical presentation has posed major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained outcomes data from the largest international registry, MSBase. We assembled cohort deeply phenotyped individuals European ancestry relapse-onset sclerosis. unbiased genome-wide association study and machine learning approaches to assess contribution longitudinally defined severity phenotypes 1813 individuals. Our primary analyses did not identify any moderate large effect sizes that met significance thresholds. The strongest signal was rs7289446 (β = −0.4882, P 2.73 × 10−7), intronic SEZ6L on chromosome 22. However, demonstrate are loci small sizes. Using approach incorporating over 62 000 together demographic variables available at onset, could predict an area under receiver operator curve 0.84 (95% CI 0.79–0.88). algorithm achieved positive predictive value outcome assignation 80% negative 88%. This outperformed our contained alone (area 0.54, 95% 0.48–0.60). Secondary, sex-stratified identified two One females (rs10967273; βfemale 0.8289, 3.52 10−8), other males (rs698805; βmale −1.5395, 4.35 providing some evidence sex dimorphism severity. Tissue enrichment pathway overrepresentation genes expressed CNS compartments generally, specifically cerebellum (P 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium G-protein receptor signalling pathways. further six strong regulating outcomes, again (adjusted hazard ratio 0.72, 4.85 10−4). Here report milestone progress towards understanding heterogeneity implicating functionally distinct mechanisms risk. Importantly, using common single nucleotide variant clusters, readily diagnosis can improve prognostic capabilities diagnosis, validation potential translate meaningful practice change.

Language: Английский

Citations

30
Alterations of the blood-brain barrier during aging DOI

Yufan Cao,

Weihai Xu,

Qing Liu

et al.

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2024, Volume and Issue: 44(6), P. 881 - 895

Published: March 21, 2024

The blood-brain barrier (BBB) is a complex and dynamic interface that regulates the exchange of molecules cells between blood central nervous system. It undergoes structural functional changes during aging, which may compromise its integrity contribute to pathogenesis neurodegenerative diseases. In recent years, advances in microscopy high-throughput bioinformatics have allowed more in-depth investigation aging mechanisms BBB. This review summarizes age-related alterations BBB structure function from six perspectives: endothelial cells, astrocytes, pericytes, basement membrane, microglia perivascular macrophages, fibroblasts, ranging molecular level human multi-system level. These basic components are essential for proper functioning Recent imaging methods were also reviewed. Elucidation age-associated offer insights into homeostasis provide effective therapeutic strategies protect it aging.

Language: Английский

Citations

8
Occurrence, synthesis and biological activity of 2-(2-phenyethyl)chromones DOI

Meiyan Fan,

Wei Yang,

Min He

et al.

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 237, P. 114397 - 114397

Published: April 19, 2022

Language: Английский

Citations

26
Nutritional components as mitigators of cellular senescence in organismal aging: a comprehensive review DOI Open Access
Bhawna Diwan, Rohit Sharma

Food Science and Biotechnology, Journal Year: 2022, Volume and Issue: 31(9), P. 1089 - 1109

Published: June 18, 2022

Language: Английский

Citations

26