An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition

Khaire, Archita; Wimberly, Courtney E; Semmes, Eleanor C; Hurst, Jillian H.; Walsh, Kyle M.

doi:10.1016/j.neurobiolaging.2022.05.011

Cited by 7 publications

(3 citation statements)

References 44 publications

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“…Metastatic BC is typically inoperable, with treatments limited to chemotherapy, hormone therapy, targeted therapy, etc., with suboptimal efficacy [9,10]. Among the strategies to combat the BC epidemic, emphasis has been placed on prevention, early diagnosis, and drug treatment [11]. Thus, identifying new reliable diagnostic biomarkers and establishing unique BC immunotherapeutic targets is paramount.…”

Section: Introductionmentioning

confidence: 99%

“…The NDUFAF6 gene is an assembly factor for the NADH ubiquinone oxidoreductase complex [6]. Previously considered c8orf38, it was first shown to be associated with mitochondrial function in 2008 [11,12]. The encoded protein is localized to the mitochondrial inner membrane and, besides playing a crucial role in the assembly of Complex I (CI) of the mitochondrial respiratory chain, it controls the synthesis of the mtDNAencoded protein ND1 [13].…”

Section: Introductionmentioning

confidence: 99%

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Impact of NDUFAF6 on breast cancer prognosis: linking mitochondrial regulation to immune response and PD-L1 expression

Jiang,

Wu,

Zeng

et al. 2024

Cancer Cell Int

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Background Breast cancer is a major global health concern, and there is a continuous search for novel biomarkers to predict its prognosis. The mitochondrial protein NDUFAF6, previously studied in liver cancer, is now being investigated for its role in breast cancer. This study aims to explore the expression and functional significance of NDUFAF6 in breast cancer using various databases and experimental models. Methods We analyzed breast cancer samples from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Human Protein Atlas (HPA) databases, supplemented with immunohistochemistry (IHC) staining to assess NDUFAF6 expression. A breast cancer cell xenograft mouse model was used to evaluate tumor growth, apoptosis, and NDUFAF6 expression. Survival probabilities were estimated through Kaplan–Meier plots and Cox regression analysis. A Protein–Protein Interaction (PPI) network was constructed, and differentially expressed genes related to NDUFAF6 were analyzed using GO, KEGG, and GSEA. The relationship between NDUFAF6 expression, immune checkpoints, and immune infiltration was also evaluated. Results NDUFAF6 was found to be overexpressed in breast cancer patients and in the xenograft mouse model. Its expression correlated with worse clinical features and prognosis. NDUFAF6 expression was an independent predictor of breast cancer outcomes in both univariate and multivariate analyses. Functionally, NDUFAF6 is implicated in several immune-related pathways. Crucially, NDUFAF6 expression correlated with various immune infiltrating cells and checkpoints, particularly promoting PD-L1 expression by inhibiting the NRF2 signaling pathway. Conclusion The study establishes NDUFAF6 as a potential prognostic biomarker in breast cancer. Its mechanism of action, involving the inhibition of NRF2 to upregulate PD-L1, highlights its significance in the disease's progression and potential as a target for immunotherapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of NDUFAF6 on breast cancer prognosis: linking mitochondrial regulation to immune response and PD-L1 expression

Jiang,

Wu,

Zeng

et al. 2024

Cancer Cell Int

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“…Conversely, pathogenic variants have been consistently found in genome-wide association study (GWAS) datasets, as factors associated with increased susceptibility to AD (Lambert et al, 2013;Tesi et al, 2020). Specifically, the Cd2ap gene is an AD-predisposition locus, substantiated by multiple GWAS with multiple populations (African American Sherva et al, 2023), Chinese (Xue et al, 2022), Northern and Western European ancestry (CEU) (Gockley et al, 2021), UK Biobank (Khaire et al, 2022;) that support the association of Cd2ap variants with small but significant increases in incidence (Amlie-Wolf et al, 2019), progression (Amlie-Wolf et al, 2019;van Bree et al, 2022), and severity (van Bree et al, 2022;Xue et al, 2022) of Alzheimer's Disease (AD). CD2AP is expressed by multiple cell types in multiple tissue types (Li et al, 2000), and may play a role in several mechanisms responsible for the pathogenesis and/or progression of AD.…”

Section: Introductionmentioning

confidence: 99%

CD2AP is Co-Expressed with Tropomyosin-Related Kinase A and Ras-Related Protein Rab-5A in Cholinergic Neurons of the Murine Basal Forebrain

Fitzsimons,

Atif-Sheikh,

Lovely

et al. 2024

Preprint

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Basal forebrain cholinergic neurons project to the hippocampus and cortex, are critical for learning and memory, and are central to the pathogenesis of Alzheimer's disease (AD). GWAS have consistently shown that genomic variants at the CD2AP gene locus are associated with significant increased risk of AD. GWAS studies have also shown that genetic variants in endocytosis genes, including RAB5A, significantly increase susceptibility to AD. Previous work in our lab has shown that CD2AP functions as a docking-scaffold/adaptor protein as a coordinator of nerve growth factor (NGF) and trophic signaling in neurons. We have also demonstrated that CD2AP positively regulates Rab5-mediated mechanisms of endocytosis in primary sensory neurons. The purpose of this study was to perform an in vivo characterization of CD2AP expression in cholinergic neurons of the brain regions most relevant to AD pathogenesis and to investigate the colocalization of CD2AP and Rab5 in cholinergic neurons of the murine basal forebrain. Brain tissue was perfused, harvested from ChATBAC-eGFP transgenic mice (N=4 male, N=4 female; aged 10 mo), where cholinergic neurons (co-) express green fluorescence protein (GFP) in central and peripheral neurons that express choline acetyltransferase (ChAT). Frozen tissue sections were used to assess the specificity of the reporter in mouse brain along with localization of both CD2AP and Rab5 (co-) expression using immunofluorescence (IF) analysis of ChAT-GFP+ neurons and primary antibodies against ChAT, CD2AP and Rab5. Image J software was used to develop and optimize a colocalization assay for CD2AP and Rab5 puncta. Experiments were repeated in a follow-up cohort of aged-adult mice (N=2 male, N=2 female; aged 18 mo). IF expression of CD2AP was quantified in the basal forebrain, diagonal band of Broca (vDB), and striatal regions and compared to results from the cortical regions of the adult mouse brain. Colocalization of CD2AP was observed in the cell bodies of ChAT-GFP+ neurons of the striatum, vDB and basal forebrain regions, where CD2AP expression intensity as well as the number of cell bodies with positive signal increased incrementally. Colocalization analyses revealed near-complete overlap of CD2AP and Rab5 expression in ChAT-GFP+ cholinergic neurons of the basal forebrain region. We conclude that cholinergic neurons express CD2AP in healthy adult and aged-adult mouse brains. These data provide the first evidence of quantifiable CD2AP protein expression of cholinergic neurons specific to the diagonal band of Broca (vDB) and basal forebrain. Together with previous research from our lab, these data support a role for CD2AP in the pathogenesis of AD through orchestration of endocytosis and retrograde signaling. Ongoing studies are underway to verify these findings in a novel AD mouse model that incorporates the humanized variant of CD2AP, created by MODEL-AD, where we aim to further investigate how CD2AP variants may affect mechanistic components of Rab5 endocytosis as well as subsequent survival of cholinergic neurons in the context of known amyloid beta and Tau pathologies.

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Genome Analysis

Onat,

Ustunel

2024

Reference Module in Life Sciences

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An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition

Cited by 7 publications

References 44 publications

Impact of NDUFAF6 on breast cancer prognosis: linking mitochondrial regulation to immune response and PD-L1 expression

Impact of NDUFAF6 on breast cancer prognosis: linking mitochondrial regulation to immune response and PD-L1 expression

CD2AP is Co-Expressed with Tropomyosin-Related Kinase A and Ras-Related Protein Rab-5A in Cholinergic Neurons of the Murine Basal Forebrain

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