Network medicine informed multiomics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis DOI Creative Commons

Mucen Yu,

Jielin Xu,

Ranjan Dutta

et al.

npj Systems Biology and Applications, Journal Year: 2024, Volume and Issue: 10(1)

Published: Nov. 5, 2024

Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on expression quantitative trait (QTL) (eQTL), protein QTL (pQTL), splicing (sQTL), methylation (meQTL), histone acetylation (haQTL). Using network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in known pathobiological pathways. Applying proximity analysis predicted drug-target networks under the protein-protein interactome (PPI) model, potential drugs (i.e., Diazoxide Gefitinib) Subsequent validation established preclinical evidence top-prioritized drugs. In summary, presented framework identify other if broadly applied.

Language: Английский

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders DOI Creative Commons
Fabiola De Marchi, Ivana Munitić,

Lea Vidatic

et al.

Biomedicines, Journal Year: 2023, Volume and Issue: 11(10), P. 2793 - 2793

Published: Oct. 14, 2023

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), well a seemingly distinct Niemann-Pick type C with primarily juvenile onset. This strongly argues for an overlap pathogenic mechanisms. The commonly researched include various cell subsets, microglia, peripheral macrophages, regulatory T cells (Tregs); the complement system; other soluble factors. In this review, we compare these diseases from clinical point of view highlight common pathways mechanisms protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies overlapping dysfunctions diseases. These approaches but not limited immunisation, cascade blockade, microbiome regulation, inhibition signal transduction, Treg boosting, stem transplantation.

Language: Английский

Citations

26
Unraveling the Genetic Landscape of Neurological Disorders: Insights into Pathogenesis, Techniques for Variant Identification, and Therapeutic Approaches DOI Open Access
Zeba Firdaus, Xiaogang Li

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 2320 - 2320

Published: Feb. 15, 2024

Genetic abnormalities play a crucial role in the development of neurodegenerative disorders (NDDs). exploration has indeed contributed to unraveling molecular complexities responsible for etiology and progression various NDDs. The intricate nature rare common variants NDDs contributes limited understanding genetic risk factors associated with them. Advancements next-generation sequencing have made whole-genome whole-exome possible, allowing identification substantial effects, improving both Mendelian complex neurological conditions. resurgence gene therapy holds promise targeting diseases ensuring sustained correction. This approach is particularly enticing diseases, where traditional pharmacological methods fallen short. In context our epidemiology three most prevalent NDDs—amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s primary goal underscore progress sequencing. aims enhance disease mechanisms explore gene-based therapies Throughout this review, we focus on variations, methodologies their identification, pathophysiology, promising potential therapy. Ultimately, objective provide comprehensive forward-looking perspective emerging research arena

Language: Английский

Citations

11
Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data DOI Creative Commons
Yanbing Wang, Chloé Sarnowski, Honghuang Lin

et al.

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

Citations

9
The 2023 yearbook of Neurorestoratology DOI Creative Commons
Hongyun Huang, John R. Bach,

Hari Shanker Sharma

et al.

Journal of Neurorestoratology, Journal Year: 2024, Volume and Issue: 12(3), P. 100136 - 100136

Published: June 13, 2024

Remarkable advancements have been made in understanding the pathogenesis of Alzheimer's disease, Parkinson's and other neurological disease; our depth neurorestorative mechanisms such as anti-inflammatory processes, immune regulation, neuromodulation, neovascularization/neural repair, neuroprotection; clinical treatments. Multiple types cell therapies reported, with some positive outcomes. Diverse forms neurostimulation neuromodulation well brain–computer interfaces shown good therapeutic outcomes applications. Further, surgery pharmaceutic therapy very impressive. These fundamental achievements are helpful for diseases neurorestoration. Patients impairments benefited from progress, but these still require confirmation higher-level randomized trials.

Language: Английский

Citations

9
Factors Affecting Resilience and Prevention of Alzheimer's Disease and Related Dementias DOI Creative Commons
Arjun V. Masurkar, Karyn Marsh, Brianna Morgan

et al.

Annals of Neurology, Journal Year: 2024, Volume and Issue: 96(4), P. 633 - 649

Published: Aug. 17, 2024

Alzheimer's disease (AD) is a devastating, age‐associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum AD spans from preclinical to subjective cognitive decline, mild impairment, dementia stages (mild, moderate, severe). Neuropathologically, defined by accumulation amyloid β (Aβ) into extracellular plaques in brain parenchyma cerebral vasculature, abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development treatment approaches prevent or even reduce decline because has been slow compared other major causes death. Recently, United States Food Drug Administration gave full approval 2 different Aβ‐targeting monoclonal antibodies. However, this breakthrough modifying approach only applies limited subset patients there are stringent eligibility criteria. Furthermore, these do not progression disease, AD‐related pathologies, such as NFTs, directly targeted. A non‐mutually exclusive alternative address lifestyle interventions can help risk dementias (ADRD). It estimated addressing modifiable factors could potentially delay up 40% AD/ADRD cases. In review, we discuss some many may be associated with prevention and/or increasing resilience, well interact influence progression. [Color figure viewed at www.annalsofneurology.org ] ANN NEUROL 2024;96:633–649

Language: Английский

Citations

8
Astaxanthin Inhibits H2O2-Induced Excessive Mitophagy and Apoptosis in SH-SY5Y Cells by Regulation of Akt/mTOR Activation DOI Creative Commons
Tingting Yan,

Feng Ding,

Yiting Zhang

et al.

Marine Drugs, Journal Year: 2024, Volume and Issue: 22(2), P. 57 - 57

Published: Jan. 24, 2024

Oxidative stress, which damages cellular components and causes mitochondrial dysfunction, occurs in a variety of human diseases, including neurological disorders. The clearance damaged mitochondria via mitophagy maintains the normal function facilitates cell survival. Astaxanthin is an antioxidant known to have neuroprotective effects, but underlying mechanisms remain unclear. This study demonstrated that astaxanthin inhibited H

Language: Английский

Citations

7
Insights into the Role of Glutathione Peroxidase 3 in Non-Neoplastic Diseases DOI Creative Commons

Nan Zhang,

Hai‐Han Liao,

Zheng Lin

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(6), P. 689 - 689

Published: June 13, 2024

Reactive oxygen species (ROSs) are byproducts of normal cellular metabolism and play pivotal roles in various physiological processes. Disruptions the balance between ROS levels body’s antioxidant defenses can lead to development numerous diseases. Glutathione peroxidase 3 (GPX3), a key component system, is an oxidoreductase enzyme. GPX3 mitigates oxidative damage by catalyzing conversion hydrogen peroxide into water. Beyond its function, vital regulating metabolism, modulating cell growth, inducing apoptosis facilitating signal transduction. It also serves as significant tumor suppressor cancers. Recent studies have revealed aberrant expression several non-neoplastic diseases, associating it with multiple pathological This review synthesizes current understanding regulation, highlighting extensive noncancerous Additionally, this paper evaluates potential diagnostic biomarker explores emerging therapeutic strategies targeting enzyme, offering avenues for future clinical treatment conditions.

Language: Английский

Citations

6
Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders DOI Open Access
Fabiola De Marchi,

Lea Vidatic,

Eliša Papić

et al.

Published: Sept. 13, 2023

Many of the potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), but also a seemingly distinct Niemann-Pick type C with primarily juvenile-onset. This strongly argues for an overlap pathogenic mechanisms. The commonly researched include various cell subsets microglia, peripheral macrophages, or regulatory T cells (Tregs), complement system, other soluble factors. In this review, we will compare these from clinical point view out common pathways mechanisms protein aggregation, neurodegeneration and/or neuroinflammation that could potentially lead to shared treatment strategies. We describe approaches treating dysfunctions disorders, moving immunization microbiome regulation stem treatment.

Language: Английский

Citations

13
Impact of APOE and MAPT genetic profile on the cognitive functions among Amyotrophic Lateral Sclerosis Tunisian patients DOI
Ikram Sghaier, Imen Kacem, Antonia Ratti

et al.

Journal of Neural Transmission, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Language: Английский

Citations

0
Investigating shared risk variants and genetic etiology between Alzheimer’s disease and three stress-related psychiatric disorders: a large-scale genome-wide cross-trait analysis DOI Creative Commons

Weijia Dang,

Tianqi Hao,

Ning Li

et al.

Frontiers in Aging, Journal Year: 2025, Volume and Issue: 6

Published: Feb. 5, 2025

Introduction Observational studies have reported that patients with Alzheimer’s disease (AD) a greater burden of comorbidities typically associated stress-related psychiatric disorders. However, the contribution hereditary factors to this comorbidity remains unclear. We evaluated phenotypic associations using observational data from UK Biobank. Method Our study focused on investigating shared risk variants and genetic etiology underlying AD three disorders: post-traumatic stress disorder, anxiety major depressive disorder. By leveraging summary statistics genome-wide association studies, we investigated global correlations linkage disequilibrium score regression, covariance analysis, high-definition likelihood. Genome-wide cross-trait analysis based subsets cross-phenotype were performed discover significant between Results A positive correlation was observed disorder regression (rg = 0.231; P 0.018), 0.138; < 0.001), likelihood 0.188; 0.001). Association revealed thirteen in six genes disorder; seven four 23 Functional annotation gene-set enrichment indicated 12 for all disorders enriched spleen, pancreas, whole blood. Conclusion These results advance our knowledge origins pave way advancements diagnosis, management, prevention AD.

Language: Английский

Citations

0