Non‐coding variants in MYH11, FZD3, and SORCS3 are associated with dementia in women

Blue, Elizabeth; Thornton, Timothy A.; Kooperberg, Charles; Liu, Simin; Wactawski‐Wende, Jean; Manson, JoAnn E.; Kuller, Lew; Hayden, Kathleen M.; Reiner, Alexander P.

doi:10.1002/alz.12181

Cited by 25 publications

(22 citation statements)

References 54 publications

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“…Among the upregulated endothelial-specific genes in Knight-C1, we identified MYOCD , CNN1 , PLN , MYH11 , S 100A4 , SLC13A4 , DES , implicating pathways associated with cell cycle, junction, anion transport, Aβ clearance and actin. In particular, MYH11 overexpressed in Knight-C4 ( Fig 7E and 7F ) has been reported to be associated with the risk of dementia [93]. Moreover, oligodendrocyte-specific genes dysregulated in Knight-C2 include STX4 (Syntaxin-4), ACTN4 , and FBXO32 relating to pathways associated with vesicle docking, neural tube, junction, apoptosis, and actin.…”

Section: Resultsmentioning

confidence: 99%

Brain cross-omics integration in Alzheimer’s disease

Eteleeb

Novotny

Soriano-Tárraga

et al. 2022

Preprint

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Clinical and molecular heterogeneity of Alzheimer disease (AD) is increasingly recognized as a major factor impacting the diagnosis, the design of therapeutic interventions and clinical trials, and therefore possibly delaying the development of effective treatments for AD. We sought to determine whether cross-omics integration reveals molecular profiles of AD with clinical and biological relevance. By leveraging cross-omics approaches, we integrated high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles from AD and control cases from multiple cortical regions and cohorts. We identified four distinct molecular profiles in which a specific profile was associated with significantly higher Clinical Dementia Rating (CDR) at death, shorter survival after onset, more severe neurodegeneration and astrogliosis, and decreased levels of metabolomic profiles. Its molecular signatures show significant dysregulation of synaptic genes indicating neuron/synapse losses and dysfunction at later stages of AD, and present in multiple cortical regions. Among other molecules, we found that the expression of alpha-synuclein (SNCA) and SNAP25 were downregulated in this profile. Overall, our results suggest that AD has a more prominent synaptic loss and dysfunction associated with worse cognition. These novel molecular findings open the possibility for new biomarkers for the molecular staging of AD and potential therapeutic targets to ameliorate cognitive decline and AD progression.

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Section: Resultsmentioning

confidence: 99%

Brain cross-omics integration in Alzheimer’s disease

Eteleeb

Novotny

Soriano-Tárraga

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…(C) The degree distribution of different types of genes in protein-protein interaction network. are altered expression in plasma, CSF, or brain of AD patients (Kitamura et al, 1997;Galimberti et al, 2006;Laske et al, 2008;Mateos et al, 2011;Xu et al, 2018;Cho et al, 2019;Meyer et al, 2019;Oeckl et al, 2019;Kuan et al, 2021); AD association of variants in or surrounding MYH11, NTRK2, PSMC3 and ISG15 have been detected (Chen et al, 2008;Roy et al, 2020;Blue et al, 2021;Novikova et al, 2021). Relationships between AD and high degree genes COL1A2, EZR, and VCAN haven't been reported, their roles in AD pathology need further study.…”

Section: Discussionmentioning

confidence: 99%

Preservation Analysis on Spatiotemporal Specific Co-expression Networks Suggests the Immunopathogenesis of Alzheimer’s Disease

Guo

Liu

Wang

2021

Front. Aging Neurosci.

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The occurrence and development of Alzheimer’s disease (AD) is a continuous clinical and pathophysiological process, molecular biological, and brain functional change often appear before clinical symptoms, but the detailed underlying mechanism is still unclear. The expression profiling of postmortem brain tissue from AD patients and controls provides evidence about AD etiopathogenesis. In the current study, we used published AD expression profiling data to construct spatiotemporal specific coexpression networks in AD and analyzed the network preservation features of each brain region in different disease stages to identify the most dramatically changed coexpression modules and obtained AD-related biological pathways, brain regions and circuits, cell types and key genes based on these modules. As result, we constructed 57 spatiotemporal specific networks (19 brain regions by three disease stages) in AD and observed universal expression changes in all 19 brain regions. The eight most dramatically changed coexpression modules were identified in seven brain regions. Genes in these modules are mostly involved in immune response-related pathways and non-neuron cells, and this supports the immune pathology of AD and suggests the role of blood brain barrier (BBB) injuries. Differentially expressed genes (DEGs) meta-analysis and protein–protein interaction (PPI) network analysis suggested potential key genes involved in AD development that might be therapeutic targets. In conclusion, our systematical network analysis on published AD expression profiling data suggests the immunopathogenesis of AD and identifies key brain regions and genes.

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“…[13] Aberrant expression of FZD3 is involved in multiple diseases, such as cancers, neurodegenerative diseases, and gynecological diseases. [14][15][16] However, the role of FZD3 in POP remains not understood.…”

Section: Introductionmentioning

confidence: 99%

FZD3 regulates the viability, apoptosis, and extracellular matrix degradation of vaginal wall fibroblasts in pelvic organ prolapse via the Wnt signaling pathway

Li,

Zhang,

Chu

et al. 2024

J Biochem & Molecular Tox

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The occurrence of pelvic organ prolapse (POP) seriously affects women's quality of life. However, the pathogenesis of POP remains unclear. We aimed to clarify the role of Frizzled class receptor 3 (FZD3) in POP. FZD3 expression in the vaginal wall tissues was detected using immunohistochemistry, real‐time polymerase chain reaction, and western blot analysis. Then, vaginal wall fibroblasts (VWFs) were isolated from patients with POP and non‐POP, and were identified. Cell viability and apoptosis were evaluated using Cell Counting Kit‐8 and flow cytometry, respectively. Extracellular matrix (ECM) degradation was assessed by western blot analysis. The results illustrated that FZD3 was downregulated in POP. VWFs from POP had lower cell viability, ECM degradation, and higher apoptosis. Knockdown of FZD3 inhibited cell viability, ECM degradation, and promoted apoptosis of VWFs, whereas overexpression of FZD3 had opposite results. Moreover, IWP‐4 (Wingless‐type [Wnt] pathway inhibitor) reversed the role of FZD3 overexpression on biological behaviors. Taken together, FZD3 facilitates VWFs viability, ECM degradation, and inhibits apoptosis via the Wnt pathway in POP. The findings provide a potential target for the treatment of POP.

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Non‐coding variants in MYH11, FZD3, and SORCS3 are associated with dementia in women

Cited by 25 publications

References 54 publications

Brain cross-omics integration in Alzheimer’s disease

Brain cross-omics integration in Alzheimer’s disease

Preservation Analysis on Spatiotemporal Specific Co-expression Networks Suggests the Immunopathogenesis of Alzheimer’s Disease

FZD3 regulates the viability, apoptosis, and extracellular matrix degradation of vaginal wall fibroblasts in pelvic organ prolapse via the Wnt signaling pathway

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