Genetic Markers of Postmortem Brain Iron

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(2)

Published: Feb. 1, 2025

ABSTRACT Brain iron (Fe) dyshomeostasis is implicated in neurodegenerative diseases. Genome‐wide association studies (GWAS) have identified plausible loci correlated with peripheral levels of Fe. Systemic organs and the brain share several Fe regulatory proteins but there likely exist different homeostatic pathways. We performed first GWAS inductively coupled plasma mass spectrometry measures postmortem from 635 Rush Memory Aging Project (MAP) participants. Sixteen single nucleotide polymorphisms (SNPs) associated at least one four regions were measured ( p < 5 × 10 −8 ). Promising SNPs −6 ) followed up for replication published blood, spleen, imaging traits mapped to candidate genes targeted cortical transcriptomic epigenetic analysis MAP. Results previously other also examined. Ninety‐eight nominally 0.05) or more related traits. Most novel had no direct links pathways rather endoplasmic reticulum‐Golgi trafficking SORL1, SORCS2, MARCH1, CLTC ), heparan sulfate HS3ST4, HS3ST1 coenzyme A SLC5A6, PANK3 ); supported by nearest gene function omic analyses. replicated mapping cellular systemic regulation. Finally, BMAL, COQ5, SLC25A11 prior PINK1, PPIF, LONP1 lend support role circadian rhythms mitochondria regulation generally. In summary, we provide linked that may greater relevance accumulation; some which are neurodegeneration. However, a subset blood suggests genetic determinants biological underlying accumulation not completely distinct those circulating periphery. image

Language: Английский

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Immunotherapeutic approach to reduce senescent cells and alleviate senescence‐associated secretory phenotype in mice

Aging Cell, Journal Year: 2023, Volume and Issue: 22(5)

Published: March 26, 2023

Abstract Accumulation of senescent cells (SNCs) with a senescence‐associated secretory phenotype (SASP) has been implicated as major source chronic sterile inflammation leading to many age‐related pathologies. Herein, we provide evidence that bifunctional immunotherapeutic, HCW9218, capabilities neutralizing TGF‐β and stimulating immune cells, can be safely administered systemically reduce SNCs alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration HCW9218 reduced islet β resulting improved glucose tolerance, insulin resistance, aging index. naturally aged mice, durably level SASP, lower expression pro‐inflammatory genes peripheral organs. treatment also reverted pattern key regulatory circadian gene mice levels observed young impacted associated metabolism fibrosis liver. Single‐nucleus RNA Sequencing analysis further revealed differentially changed transcriptomic landscape hepatocyte subtypes involving metabolic, signaling, cell‐cycle, pathways Long‐term survival studies showed physical performance without compromising health span Thus, represents novel immunotherapeutic approach clinically promising new class senotherapeutic agents targeting cellular diseases.

Language: Английский

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Sleep and sleep disorders in people with Parkinson's disease

The Lancet Neurology, Journal Year: 2024, Volume and Issue: 23(9), P. 925 - 937

Published: Sept. 1, 2024

Language: Английский

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Sleep and Oxidative Stress: Current Perspectives on the Role of NRF2

Cellular and Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 44(1)

Published: June 25, 2024

Abstract Sleep is a fundamental conserved physiological state across evolution, suggesting vital biological functions that are yet to be fully clarified. However, our understanding of the neural and molecular basis sleep regulation has increased rapidly in recent years. Among various processes implicated controlling homeostasis, bidirectional relationship between oxidative stress recently emerged. One proposed function may mitigation both brain peripheral tissues, contributing clearance reactive species accumulate during wakefulness. Conversely, species, such as oxygen (ROS) nitrogen (RNS), at levels, act signaling agents regulate redox-sensitive transcriptional factors, enzymes, other effectors involved sleep. As primary sensor intracellular oxidation, transcription factor NRF2 emerging an indispensable component maintain cellular redox homeostasis Indeed, number studies have revealed association dysfunction most common conditions, including loss, obstructive apnea, circadian disturbances. This review examines evidence intricate link context sleep, highlights potential modulators alleviate Graphical A been shown, indicating play protective role against accumulation wakefulness deprivation. might also serve molecules influence mechanisms. Notably, changes, key regulator homeostasis.

Language: Английский

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New insight on microglia activation in neurodegenerative diseases and therapeutics

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Dec. 22, 2023

Microglia are immune cells within the central nervous system (CNS) closely linked to brain health and neurodegenerative diseases such as Alzheimer’s disease Parkinson’s disease. In response changes in surrounding environment, microglia activate change their state function. Several factors, example for circadian rhythm disruption development of diseases, influence activation. this review, we explore microglia’s function associated neural mechanisms. We elucidate that rhythms essential factors influencing activation Circadian affects and, consequently, diseases. addition, found abnormal is a common feature an factor development. Here highlight importance Targeting treatment promising direction. introduce progress methods targeting summarize drugs developed with targets, hoping provide new ideas treating

Language: Английский

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