New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN

Physiological Reviews, Journal Year: 2023, Volume and Issue: 104(1), P. 399 - 472

Published: Aug. 24, 2023

Cell excitability and its modulation by hormones neurotransmitters involve the concerted action of a large repertoire membrane proteins, especially ion channels. Unique complements coexpressed channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that tailored for diverse physiological contributions, dysfunction any component may induce disease state. A crucial parameter controlling is resting potential (RMP) set extra- intracellular concentrations ions, mainly Na + , K Cl − their passive permeation across through leak Indeed, dysregulation RMP causes significant effects on cellular excitability. This review describes molecular channel NALCN, which associates with accessory subunits UNC-79, UNC-80, NLF-1/FAM155 to conduct depolarizing background currents various neurons. Studies animal models clearly demonstrate NALCN contributes fundamental processes nervous system including control respiratory rhythm, circadian sleep, locomotor behavior. Furthermore, associated severe pathological states humans. The critical involvement physiology now well established, but study has been hampered lack specific drugs can block or agonize vitro vivo. Molecular tools available accelerate our understanding how key functions development novel therapies channelopathies.

Language: Английский

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Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(5), P. 3290 - 3304

Published: March 21, 2024

Abstract INTRODUCTION Genome‐wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire and captures rare variations, may GWAS METHODS We performed single common variant analysis aggregate analyses in pooled population ( N cases = 2184, controls 2383) targeted subpopulations using WGS data from Disease Sequencing Project (ADSP). The were restricted to 100 kb 83 previously lead variants. RESULTS Seventeen significantly AD five genomic regions implicating OARD1 / NFYA TREML1 , JAZF1 FERMT2 SLC24A4 . KAT8 was implicated by both analyses. DISCUSSION This study demonstrates utility leveraging gain insights into via GWAS.

Language: Английский

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Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases

Genes, Journal Year: 2025, Volume and Issue: 16(2), P. 135 - 135

Published: Jan. 24, 2025

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s (PD), Huntington’s (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression significant impact on patients, caregivers, healthcare systems. Despite advances in clinical imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs genomic transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), CRISPR-based screens, have revolutionized field, offering new avenues for early diagnosis personalized prognosis. Genomic approaches elucidated disease-specific genetic risk factors molecular pathways, while studies identified stage-specific biomarkers that correlate with severity. Furthermore, genome-wide association (GWAS), polygenic scores (PRS), spatial transcriptomics enabling stratification patients based profiles prognostic trajectories. Advances functional genomics uncovered actionable targets, ATXN2 ALS TREM2 AD, paving way tailored strategies. achievements, challenges remain translating discoveries into practice heterogeneity complexity neurodegenerative pathophysiology. Future integration technologies holds promise transforming diagnostic paradigms, hope improved patient outcomes precision medicine approaches.

Language: Английский

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Alzheimer's disease risk ABCA7 p.A696S variant disturbs the microglial response to amyloid pathology in mice

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106813 - 106813

Published: Jan. 1, 2025

Language: Английский

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Identification of 16 novel Alzheimer's disease loci using multi‐ancestry meta‐analyses

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(2)

Published: Feb. 1, 2025

Abstract INTRODUCTION Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD‐associated genetic determinants have been identified, few studies analyzed individuals non‐European ancestry. METHODS We conducted a multi‐ancestry genome‐wide association study (GWAS) clinically diagnosed AD and AD‐by‐proxy using whole genome sequencing data from National Institute on Aging Genetics Disease Data Storage Site (NIAGADS), Mental Health, UK Biobank (UKB), All Us (AoU) consisting 49,149 cases (12,074 37,075 AD‐by‐proxy) 383,225 controls. Nearly half NIAGADS AoU participants were RESULTS For AD, we identified 14 new loci—five common (FBN2/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) nine rare (VWA5B1, RNU6‐755P/LMX1A, MOB1A, MORC1‐AS1, LINC00989, PDE4D, RNU2‐49P/CDO1, NEO1, SLC35G3/AC022916.1). Meta‐analysis UKB yielded two loci (RPL23/LASP1 CEBPA/AC008738.6), also nominally significant in NIAGADS. DISCUSSION In summary, provide evidence for 16 novel advocate more sequencing–based GWAS diverse cohorts. Highlights used whole‐genome large found findings based data. performed multiancestry meta‐analysis incorporated results underrepresented groups.

Language: Английский

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Genomics and Functional Genomics of Alzheimer's Disease

Neurotherapeutics, Journal Year: 2021, Volume and Issue: 19(1), P. 152 - 172

Published: Dec. 21, 2021

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease. Due to its long clinical course lack of an effective treatment, AD has become major public health problem in the USA worldwide. variation age-at-onset, classified into early-onset (< 60 years) late-onset (≥ forms with accounting for only 5-10% all cases. With exception small number cases that are afflicted because high penetrant single gene mutations APP, PSEN1, PSEN2 genes, genetically heterogeneous, especially form having polygenic or oligogenic risk inheritance. Since identification APOE as most significant factor 1993, path discovery additional genes had been arduous until 2009 when use large genome-wide association studies opened up gateways led ~ 95 loci from early 2022. This article reviews history genetics followed by potential molecular pathways recent application functional genomics methods identify causal gene(s) among many reside within locus. The ultimate goal integrating discover novel underlying pathobiology order drug targets therapeutic treatment this heterogeneous disorder.

Language: Английский

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Stearoyl-CoA Desaturase inhibition reverses immune, synaptic and cognitive impairments in an Alzheimer’s disease mouse model

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: April 20, 2022

Abstract The defining features of Alzheimer’s disease (AD) include alterations in protein aggregation, immunity, lipid metabolism, synapses, and learning memory. Of these, abnormalities are the least understood. Here, we investigate role Stearoyl-CoA desaturase (SCD), a crucial regulator fatty acid desaturation, AD pathogenesis. We show that inhibiting brain SCD activity for 1-month 3xTg mouse model alters core AD-related transcriptomic pathways hippocampus, it concomitantly restores essential components hippocampal function, including dendritic spines structure, immediate-early gene expression, memory itself. Moreover, inhibition dampens activation microglia, key mediators spine loss during main immune cells brain. These data reveal metabolism links genes to downstream immune, synaptic, functional impairments, identifying as potential target treatment.

Language: Английский

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Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Jan. 9, 2022

Abstract The search for rare variants in Alzheimer’s disease (AD) is usually deemed a high-risk - high-reward situation. challenges associated with this endeavor are real. Still, the application of genome-wide technologies to large numbers cases and controls or small, well-characterized families has started be fruitful. Rare AD have been shown increase risk cause disease, but also protect against development AD. All these can potentially targeted new drugs. Multiple independent studies now associations NOTCH3 , TREM2 SORL1 ABCA7 BIN1 CLU NCK2 AKAP9 UNC5C PLCG2, ABI3 suggested that they may influence via multiple mechanisms. These genes reported functions immune system, lipid metabolism, synaptic plasticity, apoptosis. However, main pathway emerging from collective harboring Aβ pathway. Associations dozens other proposed, not yet replicated studies. Replication type findings one studying complex diseases, such as In review, we discuss some primary well possible solutions. Integrative approaches, availability datasets databases, analytical methodologies will continue produce variability impacting future, more extensive diverse genetic studies, deeply characterized families, enhance our understanding pathogenesis put us on correct path successful

Language: Английский

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Identification of 16 novel Alzheimer's disease susceptibility loci using multi-ancestry meta-analyses of clinical Alzheimer's disease and AD-by-proxy cases from four whole genome sequencing datasets

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 12, 2024

Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been previously identified, few studies analyzed individuals non-European ancestry. Here, we describe a multi-ancestry genome-wide association study clinically-diagnosed AD and AD-by-proxy using whole genome sequencing data from NIAGADS, NIMH, UKB, All Us (AoU) consisting 49,149 cases (12,074 37,075 AD-by-proxy) 383,225 controls. Nearly half NIAGADS AoU participants are For AD, identified 14 new loci - five common (

Language: Английский

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Mitochondrial Electron Transport Chain Protein Abnormalities Detected in Plasma Extracellular Vesicles in Alzheimer’s Disease

Biomedicines, Journal Year: 2021, Volume and Issue: 9(11), P. 1587 - 1587

Published: Oct. 31, 2021

Mitochondria provide energy to neurons through oxidative phosphorylation and eliminate Reactive Oxygen Species (ROS) Superoxide Dismutase 1 (SOD1). Dysfunctional mitochondria, manifesting decreased activity of electron transport chain (ETC) complexes high ROS levels, are involved in Alzheimer's disease (AD) pathogenesis. We hypothesized that neuronal mitochondrial dysfunction AD is reflected ETC SOD1 levels plasma neuron-derived extracellular vesicles (NDEVs). immunoprecipitated NDEVs targeting marker L1CAM from two cohorts: one including 22 individuals with early 29 control subjects; another 14 subjects. In the first cohort, we measured I, III, IV, ATP synthase, SOD1; second catalytic IV synthase. had lower I (p < 0.0001), III = 0.0061), V 0.0001) compared controls. also complex 0.0214) synthase 0.0001). confirm quantitative functional abnormalities ECT previously observed models during autopsy, opening way for using them as biomarkers AD.

Language: Английский

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