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Biomolecules
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Applications and Advances of Omics and Bioinformatics in the Research...
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Applications and Advances of Omics and Bioinformatics in the Research of Alzheimer’s Disease and Complex Phenotypes

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Bioinformatics and Systems Biology".

Deadline for manuscript submissions: closed (20 August 2023) | Viewed by 6667

Special Issue Editor

Dr. Perry G. Ridge

E-Mail Website
Guest Editor
Department of Biology, Brigham Young University, Provo, UT, USA
Interests: Alzheimer's association; bioinformatics; genetics; genomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Late-onset Alzheimer’s disease is a complex trait that is challenging to diagnose, nearly impossible to predict before the onset of symptoms and has no effective treatments. As a multi-faceted trait, the solutions will likely require innovation from many different areas of disease research. One challenge we seek to address here is solving the genetic architecture of complex traits. Significant efforts have been made to understand the genetics of Alzheimer’s disease. However, although estimates vary, we still cannot explain most of the heritability of Alzheimer’s disease with known genetic risk factors. Large sequencing projects exist and are underway (e.g., the Alzheimer’s Disease Sequencing Project), and datasets are being expanded to include transcriptomes, proteomes, metabolomes, etc. Although we specifically described Alzheimer’s disease here, similar datasets and challenges exist for many diseases, and computational advances are likely to be widely applicable. We seek manuscripts that describe novel methods for interrogating any or all omics data to find disease markers or provide insights into disease processes, or the application of computational approaches to research Alzheimer’s disease or other complex traits.

Dr. Perry G. Ridge
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • bioinformatics
  • genomics
  • Alzheimer’s disease
  • complex phenotypes
  • multi-omics
  • methods

Published Papers (2 papers)

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Research

22 pages, 4060 KiB  
Article
Proteomic Signaling of Dual-Specificity Phosphatase 4 (DUSP4) in Alzheimer’s Disease
by Erming Wang, Allen L. Pan, Pritha Bagchi, Srikant Rangaraju, Nicholas T. Seyfried, Michelle E. Ehrlich, Stephen R. Salton and Bin Zhang
Biomolecules 2024, 14(1), 66; https://doi.org/10.3390/biom14010066 - 03 Jan 2024
Viewed by 1298
Abstract
DUSP4 is a member of the DUSP (dual-specificity phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer’s disease (AD). In this study, we utilized the stereotactic delivery [...] Read more.
DUSP4 is a member of the DUSP (dual-specificity phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer’s disease (AD). In this study, we utilized the stereotactic delivery of adeno-associated virus (AAV)-DUSP4 to overexpress DUSP4 in the dorsal hippocampus of 5xFAD and wildtype (WT) mice, then used mass spectrometry (MS)-based proteomics along with the label-free quantification to profile the proteome and phosphoproteome in the hippocampus. We identified protein expression and phosphorylation patterns modulated in 5xFAD mice and examined the sex-specific impact of DUSP4 overexpression on the 5xFAD proteome/phosphoproteome. In 5xFAD mice, a substantial number of proteins were up- or down-regulated in both male and female mice in comparison to age and sex-matched WT mice, many of which are involved in AD-related biological processes, such as activated immune response or suppressed synaptic activities. Many proteins in pathways, such as immune response were found to be suppressed in response to DUSP4 overexpression in male 5xFAD mice. In contrast, such a shift was absent in female mice. For the phosphoproteome, we detected an array of phosphorylation sites regulated in 5xFAD compared to WT and modulated via DUSP4 overexpression in each sex. Interestingly, 5xFAD- and DUSP4-associated phosphorylation changes occurred in opposite directions. Strikingly, both the 5xFAD- and DUSP4-associated phosphorylation changes were found to be mostly in neurons and play key roles in neuronal processes and synaptic functions. Site-centric pathway analysis revealed that both the 5xFAD- and DUSP4-associated phosphorylation sites were enriched for a number of kinase sets in females but only a limited number of sets of kinases in male mice. Taken together, our results suggest that male and female 5xFAD mice responded to DUSP4 overexpression via shared and sex-specific molecular mechanisms, which might underly similar reductions in amyloid pathology in both sexes while learning deficits were reduced in only females with DUSP4 overexpression. Finally, we validated our findings with the sex-specific AD-associated proteomes in human cohorts and further developed DUSP4-centric proteomic network models and signaling maps for each sex. Full article
(This article belongs to the Special Issue Applications and Advances of Omics and Bioinformatics in the Research of Alzheimer’s Disease and Complex Phenotypes)
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23 pages, 21053 KiB  
Article
Large-Scale Integration of Single-Cell RNA-Seq Data Reveals Astrocyte Diversity and Transcriptomic Modules across Six Central Nervous System Disorders
by Zhenwei Qian, Jinglin Qin, Yiwen Lai, Chen Zhang and Xiannian Zhang
Biomolecules 2023, 13(4), 692; https://doi.org/10.3390/biom13040692 - 19 Apr 2023
Cited by 3 | Viewed by 5023
Abstract
The dysfunction of astrocytes in response to environmental factors contributes to many neurological diseases by impacting neuroinflammation responses, glutamate and ion homeostasis, and cholesterol and sphingolipid metabolism, which calls for comprehensive and high-resolution analysis. However, single-cell transcriptome analyses of astrocytes have been hampered [...] Read more.
The dysfunction of astrocytes in response to environmental factors contributes to many neurological diseases by impacting neuroinflammation responses, glutamate and ion homeostasis, and cholesterol and sphingolipid metabolism, which calls for comprehensive and high-resolution analysis. However, single-cell transcriptome analyses of astrocytes have been hampered by the sparseness of human brain specimens. Here, we demonstrate how large-scale integration of multi-omics data, including single-cell and spatial transcriptomic and proteomic data, overcomes these limitations. We created a single-cell transcriptomic dataset of human brains by integration, consensus annotation, and analyzing 302 publicly available single-cell RNA-sequencing (scRNA-seq) datasets, highlighting the power to resolve previously unidentifiable astrocyte subpopulations. The resulting dataset includes nearly one million cells that span a wide variety of diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), epilepsy (Epi), and chronic traumatic encephalopathy (CTE). We profiled the astrocytes at three levels, subtype compositions, regulatory modules, and cell–cell communications, and comprehensively depicted the heterogeneity of pathological astrocytes. We constructed seven transcriptomic modules that are involved in the onset and progress of disease development, such as the M2 ECM and M4 stress modules. We validated that the M2 ECM module could furnish potential markers for AD early diagnosis at both the transcriptome and protein levels. In order to accomplish a high-resolution, local identification of astrocyte subtypes, we also carried out a spatial transcriptome analysis of mouse brains using the integrated dataset as a reference. We found that astrocyte subtypes are regionally heterogeneous. We identified dynamic cell–cell interactions in different disorders and found that astrocytes participate in key signaling pathways, such as NRG3-ERBB4, in epilepsy. Our work supports the utility of large-scale integration of single-cell transcriptomic data, which offers new insights into underlying multiple CNS disease mechanisms where astrocytes are involved. Full article
(This article belongs to the Special Issue Applications and Advances of Omics and Bioinformatics in the Research of Alzheimer’s Disease and Complex Phenotypes)
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