Network-based drug repurposing for psychiatric disorders using single-cell genomics DOI
Chirag Gupta, Noah Cohen Kalafut, Declan Clarke

et al.

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

Published: Dec. 2, 2024

Neuropsychiatric disorders lack effective treatments due to a limited understanding of underlying cellular and molecular mechanisms. To address this, we integrated population-scale single-cell genomics data analyzed cell-type-level gene regulatory networks across schizophrenia, bipolar disorder, autism (23 cell classes/subclasses). Our analysis revealed potential druggable transcription factors co-regulating known risk genes that converge into cell-type-specific co-regulated modules. We applied graph neural on those modules prioritize novel leveraged them in network-based drug repurposing framework identify 220 molecules with the for targeting specific types. found evidence 37 these drugs reversing disorder-associated transcriptional phenotypes. Additionally, discovered 335 drug-associated cell-type eQTLs, revealing genetic variation's influence target expression at level. results provide network medicine resource provides mechanistic insights advancing treatment options neuropsychiatric disorders.

Language: Английский

CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis DOI Creative Commons

Avi J. Samelson,

Nabeela Ariqat, Justin McKetney

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 17, 2023

Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to aggregation subsequent dysfunction death, but underlying mechanisms unknown. To systematically uncover cellular factors controlling accumulation aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen iPSC-derived neurons. The uncovered expected pathways, including autophagy, also unexpected UFMylation GPI anchor synthesis. We discover that E3 ubiquitin ligase CUL5

Language: Английский

Citations

24
The Expanding Burden of Neurodegenerative Diseases: An Unmet Medical and Social Need DOI Creative Commons
Shu Wang,

Yin Jiang,

Anchao Yang

et al.

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2024

Neurodegenerative diseases, particularly Alzheimer's disease and other dementias as well Parkinson's disease, are emerging profoundly significant challenges burdens to global health, a trend highlighted by the most recent Global Burden of Disease (GBD) 2021 studies. This growing impact is closely linked demographic shift toward an aging population potential long-term repercussions COVID-19 pandemic, both which have intensified prevalence severity these conditions. In this review, we explore several critical aspects complex issue, including increasing burden neurodegenerative unmet medical social needs within current care systems, unique amplified posed strategies for enhancing healthcare policy practice. We underscore urgent need cohesive, multidisciplinary approaches across medical, research, domains effectively address thereby improving quality life patients their caregivers.

Language: Английский

Citations

8
Chromatin accessibility provides a window into the genetic etiology of human brain disease DOI
Jaroslav Bendl, John F. Fullard, Kiran Girdhar

et al.

Trends in Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
CoTF-reg reveals cooperative transcription factors in oligodendrocyte gene regulation using single-cell multi-omics DOI Creative Commons
Jerome Choi, John Svaren, Daifeng Wang

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Feb. 5, 2025

Oligodendrocytes are the myelinating cells within central nervous system, but mechanisms by which transcription factors (TFs) cooperate for gene regulation in oligodendrocytes remain unclear. We introduce coTF-reg, an analytical framework that integrates scRNA-seq and scATAC-seq data to identify cooperative TFs co-regulating target (TG). First, we co-binding TF pairs same oligodendrocyte-specific regulatory regions. Next, train a deep learning model predict each TG expression using TFs' expressions. Shapley interaction scores reveal high interactions between pairs, such as SOX10-TCF12. Validation oligodendrocyte eQTLs their eGenes regulated these show potential roles genetic variants. Experimental validation ChIP-seq confirms some SOX10-OLIG2. Prediction performance of our models is evaluated through holdout additional datasets, ablation study also conducted. The results demonstrate stable consistent performance. authors regulate genes cooperatively oligodendrocytes.

Language: Английский

Citations

0
Integrative Epigenomic Landscape of Alzheimer's Disease Brains Reveals Oligodendrocyte Molecular Perturbations Associated with Tau DOI Open Access

Stephanie R. Oatman,

Joseph S. Reddy,

Amin Atashgaran

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract Alzheimer’s disease (AD) brains are characterized by neuropathologic and biochemical changes that highly variable across individuals. Capturing epigenetic factors associate with this variability can reveal novel biological insights into AD pathophysiology. We conducted an epigenome-wide association study of DNA methylation (DNAm) in 472 measures (Braak stage, Thal phase, cerebral amyloid angiopathy score) brain levels five proteins (APOE, amyloid-β (Aβ)40, Aβ42, tau, p-tau) core to pathogenesis. Using a regional (rCpGm) approach, we identified 5,478 significant associations, 99.7% which were tau measures. Of the tau-associated rCpGms, 93 had concordant associations external datasets comprising 1,337 samples. Integrative transcriptome-methylome analyses uncovered 535 gene expression for these rCpGms. Genes concurrent perturbations enriched oligodendrocyte marker genes, including known risk genes such as BIN1 , myelination MYRF, MBP MAG previously implicated AD, well like LDB3 . further annotated top additional 6 single cell 2 bulk transcriptome from two other tauopathies, Pick’s progressive supranuclear palsy (PSP). Our findings support consistent rCpGm tauopathies tau-related phenotypes both tissue clusters. In summary, uncover integrative epigenomic landscape demonstrate common potential pathomechanism different tauopathies.

Language: Английский

Citations

0
The Genetic Background of the Immunological and Inflammatory Aspects of Progressive Supranuclear Palsy DOI Open Access
Piotr Alster, Natalia Madetko‐Alster

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 3927 - 3927

Published: April 22, 2025

Progressive supranuclear palsy (PSP) is a neurodegenerative disease, classified as an atypical Parkinsonian syndrome, that has been pathologically and clinically defined. The histopathological aspects of the disease include tufted astrocytes, while clinical features involve oculomotor dysfunction, postural instability, akinesia, cognitive impairment, language difficulties. Although PSP generally considered sporadic interest growing in its genetics, with contemporary research focusing on familial backgrounds neuroinflammation. Indeed, microglial activation other inflammatory mechanisms pathogenesis have extensively analyzed using genetic examinations to identify factors impacting neurodegeneration. As such, this review aims elaborate recent findings field.

Language: Английский

Citations

0
Multisensory gamma stimulation enhances adult neurogenesis and improves cognitive function in male mice with Down Syndrome DOI Creative Commons
Md. Rezaul Islam, Brennan Jackson,

Maeesha Tasnim Naomi

et al.

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(4), P. e0317428 - e0317428

Published: April 24, 2025

Language: Английский

Citations

0
NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome DOI Creative Commons
Hossein Khodadadi,

Kamila Łuczyńska,

Dawid Winiarczyk

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 18

Published: May 1, 2025

Maintaining proteostasis is critical for neuronal health, with its disruption underpinning the progression of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Nuclear Factor Erythroid 2-Related 1 (NFE2L1) has emerged a key regulator proteostasis, integrating proteasome function, autophagy, ferroptosis to counteract oxidative stress protein misfolding. This review synthesizes current knowledge on role NFE2L1 in maintaining homeostasis, focusing mechanisms mitigating proteotoxic supporting cellular offering protection against neurodegeneration. Furthermore, we discuss pathological implications dysfunction explore potential therapeutic target. By highlighting gaps understanding presenting future research directions, this aims elucidate NFE2L1’s advancing treatment strategies

Language: Английский

Citations

0
Cell States and Interactions of CD8 T Cells and Disease-Enriched Microglia in Human Brains with Alzheimer’s Disease DOI Creative Commons
Mai Yamakawa, Jessica E. Rexach

Biomedicines, Journal Year: 2024, Volume and Issue: 12(2), P. 308 - 308

Published: Jan. 29, 2024

Alzheimer's disease (AD) is a multi-stage neurodegenerative disorder characterized by beta-amyloid accumulation, hyperphosphorylated Tau deposits, neurodegeneration, neuroinflammation, and cognitive impairment. Recent studies implicate CD8 T cells as neuroimmune responders to the accumulation of AD pathology in brain potential contributors toxic neuroinflammation. However, more evidence needed understand lymphocytes disease, including their functional states, molecular mediators, interacting cell types diseased tissue. The scarcity tissue samples has limited unbiased profiling disease-associated types, drug targets, relationships common genetic risk variants based on transcriptomic analyses. using recent large-scale, high-quality single-nuclear sequencing datasets from over 84 control cases, we leverage RNAseq data 800 collected 70 individuals complete profiling. We demonstrate that effector memory are major lymphocyte subclass enriched tissues with dementia. define disease-enriched interactions involving multiple subclasses two distinct microglial states correlate, respectively, tau pathology. find beta-amyloid-associated microglia hub multicellular cross-talk gained both vulnerable neuronal subtypes cells. reproduce prior reports amyloid-response depleted

Language: Английский

Citations

3
Network-based drug repurposing for psychiatric disorders using single-cell genomics DOI
Chirag Gupta, Noah Cohen Kalafut, Declan Clarke

et al.

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

Published: Dec. 2, 2024

Neuropsychiatric disorders lack effective treatments due to a limited understanding of underlying cellular and molecular mechanisms. To address this, we integrated population-scale single-cell genomics data analyzed cell-type-level gene regulatory networks across schizophrenia, bipolar disorder, autism (23 cell classes/subclasses). Our analysis revealed potential druggable transcription factors co-regulating known risk genes that converge into cell-type-specific co-regulated modules. We applied graph neural on those modules prioritize novel leveraged them in network-based drug repurposing framework identify 220 molecules with the for targeting specific types. found evidence 37 these drugs reversing disorder-associated transcriptional phenotypes. Additionally, discovered 335 drug-associated cell-type eQTLs, revealing genetic variation's influence target expression at level. results provide network medicine resource provides mechanistic insights advancing treatment options neuropsychiatric disorders.

Language: Английский

Citations

1