Multimodal joint deconvolution and integrative signature selection in proteomics DOI Creative Commons
Yue Pan, Xusheng Wang, Chunyu Liu

et al.

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

Published: Oct. 6, 2023

Abstract Deconvolution is an efficient approach for detecting cell-type-specific (cs) transcriptomic signals without cellular segmentation. However, this type of methods have not been extended to the proteomics research. Here we present a novel algorithm and tool dissect bulk proteome by leveraging information shared between transcriptome-proteome. Our first identifies potential cell marker proteins integrating RNA protein expression profiles then jointly quantifies abundance in mixture proteomes using reference signature matrix, enabling downstream analyses such as cs-protein Quantitative Trait Loci (cspQTL) mapping. This new method cspQTL analysis are implemented R package MIC-SQTL that also provides integrative visualization multimodal samples, available at https://bioconductor.org/packages/MICSQTL .

Language: Английский

Human Alzheimer’s disease reactive astrocytes exhibit a loss of homeostastic gene expression DOI Creative Commons
David Dai, Mingyao Li, Edward B. Lee

et al.

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: Aug. 2, 2023

Astrocytes are one of the brain's major cell types and responsible for maintaining neuronal homeostasis via regulating extracellular environment, providing metabolic support, modulating synaptic activity. In neurodegenerative diseases, such as Alzheimer's disease, astrocytes can take on a hypertrophic appearance. These reactive canonically associated with increases in cytoskeletal proteins, glial fibrillary acidic protein vimentin. However, molecular alterations that characterize human disease tissues have not been extensively studied single resolution. Using nucleus RNA sequencing data from normal, pathologic aging, brains, we identified transcriptomic changes astrocytes. Deep learning-based clustering algorithms denoised expression 17,012 genes clustered 15,529 astrocyte nuclei, identifying protoplasmic, gray matter fibrous, white clusters. trajectory analyses revealed spectrum reactivity within protoplasmic characterized by modest increase marked decrease homeostatic genes. Amyloid but tau pathology correlated reactivity. To identify reactivity-associated genes, linear regressions gene versus were used to top 52 upregulated 144 downregulated Gene Ontology analysis cellular growth, responses metal ions, inflammation, proteostasis. Downregulated involved interactions, development, ERBB signaling, synapse regulation. Transcription factors significantly enriched among co-immunofluorescence staining brain tissues, confirmed downregulation ERBB4 transcription factor NFIA Our findings reveal exist is strong loss normal function.

Language: Английский

Citations

43
The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research DOI Creative Commons
Takumi Nakamura, Atsushi Takata

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(5), P. 1868 - 1889

Published: March 6, 2023

Despite enormous efforts employing various approaches, the molecular pathology in schizophrenia brain remains elusive. On other hand, knowledge of association between disease risk and changes DNA sequences, words, our understanding genetic schizophrenia, has dramatically improved over past two decades. As consequence, now we can explain more than 20% liability to by considering all analyzable common variants including those with weak or no statistically significant association. Also, a large-scale exome sequencing study identified single genes whose rare mutations substantially increase for which six (SETD1A, CUL1, XPO7, GRIA3, GRIN2A, RB1CC1) showed odds ratios larger ten. Based on these findings together preceding discovery copy number (CNVs) similarly large effect sizes, multiple models high etiological validity have been generated analyzed. Studies brains models, as well transcriptomic epigenomic analyses patient postmortem tissues, provided new insights into schizophrenia. In this review, overview current acquired from studies, their limitations, directions future research that may redefine based biological alterations responsible organ rather operationalized criteria.

Language: Английский

Citations

27
Blood–Brain Barrier Disruption in Schizophrenia: Insights, Mechanisms, and Future Directions DOI Open Access
Fangsong Zhang, Jianye Zhang,

Xuexue Wang

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 873 - 873

Published: Jan. 21, 2025

The blood–brain barrier (BBB) plays a crucial role in maintaining the homeostasis of central nervous system by regulating solute transport and preventing neurotoxic substances from infiltrating brain tissue. In schizophrenia, emerging evidence identifies BBB dysfunction as key pathophysiological factor associated with neuroinflammation, tight junction abnormalities, endothelial dysfunction. Recent advancements neuroimaging techniques, such arterial spin labeling (ASL), have provided valuable tools for investigating permeability its disease progression. This review synthesizes findings postmortem studies, serum cerebrospinal fluid biomarker analyses, advanced research to elucidate alterations schizophrenia. It highlights mechanistic roles protein dysregulation, neurovascular unit dysfunction, immune responses disrupting integrity. Furthermore, examines bidirectional effects antipsychotic medications on BBB, addressing both therapeutic opportunities potential challenges. By emphasizing pivotal schizophrenia pathogenesis, this underscores translational potential. Through integration multidisciplinary evidence, it lays foundation innovative diagnostic approaches strategies, enhancing our understanding schizophrenia’s complex pathophysiology.

Language: Английский

Citations

1
Spatially resolved gene signatures of white matter lesion progression in multiple sclerosis DOI
Astrid M. Alsema, Marion H. C. Wijering, Anneke Miedema

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 5, 2024

Language: Английский

Citations

7
Unraveling Psychiatric Disorders through Neural Single-Cell Transcriptomics Approaches DOI Open Access
Samar N. Chehimi, Richard C. Crist, Benjamin C. Reiner

et al.

Genes, Journal Year: 2023, Volume and Issue: 14(3), P. 771 - 771

Published: March 22, 2023

The development of single-cell and single-nucleus transcriptome technologies is enabling the unraveling molecular cellular heterogeneity psychiatric disorders. complexity brain relationships between different regions can be better understood through classification individual cell populations based on their markers transcriptomic features. Analysis these unique types explain involvement in pathology Recent studies both human animal models have emphasized importance analysis neuronal cells disorders but also revealed critical roles for non-neuronal cells, such as oligodendrocytes microglia. In this review, we update current findings explore addressing alterations identified depression stress, neurodegenerative (Parkinson’s Alzheimer’s disease), schizophrenia, opioid use disorder, alcohol psychostimulant abuse. We comment potential future directions studies.

Language: Английский

Citations

10
Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia DOI Creative Commons
A. Wilson,

Michelle M. Jacobs,

Tova Y. Lambert

et al.

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

Published: Feb. 6, 2025

Abstract For people with HIV (PWH), substance use disorders (SUDs) are a prominent neurological risk factor, and the impacts of both on dopaminergic pathways potential point deleterious convergence. Here, we profile, at single nucleus resolution, substantia nigra (SN) transcriptomes 90 postmortem donors in context chronic opioid/cocaine SUD, including 67 prospectively characterized PWH. We report altered microglial expression for hundreds pro- anti-inflammatory regulators attributable to HIV, separately, SUD. Stepwise, progressive dysregulation, coupled SN GABAergic signaling, was associated SUD/HIV dual diagnosis further lack viral suppression blood. In virologically suppressed donors, SUD comorbidity transcriptional changes permissive infection. HIV-related downregulation monoamine reuptake transporters specifically neurons regardless status or load, additional signatures consistent selective vulnerability dopamine neurons.

Language: Английский

Citations

0
Transcriptional evidence of reduced BDNF trophic capacity in the post-mortem human midbrain of schizophrenia cases with high inflammation DOI Creative Commons

Jessica J Chandra,

Yunting Zhu, Alice Petty

et al.

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: May 7, 2025

Language: Английский

Citations

0
Involvement of an Aberrant Vascular System in Neurodevelopmental, Neuropsychiatric, and Neuro-Degenerative Diseases DOI Creative Commons
Keiichi Ishihara, Kazuyuki Takata, Ken‐ichi Mizutani

et al.

Life, Journal Year: 2023, Volume and Issue: 13(1), P. 221 - 221

Published: Jan. 12, 2023

The vascular system of the prenatal brain is crucial for development central nervous system. Communication between vessels and neural cells bidirectional, dysfunctional communication can lead to neurodevelopmental diseases. In present review, we introduce neuropsychiatric diseases potentially caused by disturbances in neurovascular discuss candidate genes responsible impairments. contrast that manifest during developing stage, have also summarized neurodegenerative including Alzheimer’s disease Parkinson’s disease. Furthermore, discussed role abnormal vascularization neurovascular-related

Language: Английский

Citations

7
Immune System and Brain/Intestinal Barrier Functions in Psychiatric Diseases: Is Sphingosine-1-Phosphate at the Helm? DOI Open Access
David Martín‐Hernández, Marina Muñoz‐López, Hiram Tendilla‐Beltrán

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12634 - 12634

Published: Aug. 10, 2023

Over the past few decades, extensive research has shed light on immune alterations and significance of dysfunctional biological barriers in psychiatric disorders. The leaky gut phenomenon, intimately linked to integrity both brain intestinal barriers, may play a crucial role origin peripheral central inflammation these pathologies. Sphingosine-1-phosphate (S1P) is bioactive lipid that regulates response permeability barriers. Notably, S1P-based drugs, such as fingolimod ozanimod, have received approval for treating multiple sclerosis, an autoimmune disease nervous system (CNS), ulcerative colitis, inflammatory condition colon, respectively. Although precise mechanisms action are still under investigation, effectiveness drugs pathologies sparks debate extending their use psychiatry. This comprehensive review aims delve into molecular through which S1P modulates brain/intestinal barrier functions. Furthermore, it will specifically focus diseases, with primary objective uncovering potential innovative therapies based signaling.

Language: Английский

Citations

5
Multimodal joint deconvolution and integrative signature selection in proteomics DOI Creative Commons
Yue Pan, Xusheng Wang,

Jiao Sun

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: April 24, 2024

Abstract Deconvolution is an efficient approach for detecting cell-type-specific (cs) transcriptomic signals without cellular segmentation. However, this type of methods may require a reference profile from the same molecular source and tissue type. Here, we present method to dissect bulk proteome by leveraging tissue-matched transcriptome using proteomics panel. Our also selects proteins contributing heterogeneity shared between proteome. The deconvoluted result enables downstream analyses such as cs-protein Quantitative Trait Loci (cspQTL) mapping. We benchmarked performance multimodal deconvolution through CITE-seq pseudo data, simulation study, multi-omics data human brain normal tissues breast cancer tumors, individually, showing robust accurate cell abundance quantification across different datasets. This algorithm implemented in tool MICSQTL that provides cspQTL integrative visualization, available at https://bioconductor.org/packages/MICSQTL .

Language: Английский

Citations

1