PLA2G7: a new player in shaping energy metabolism and lifespan

Becker, Svea

doi:10.1038/s41392-022-01052-5

Cited by 3 publications

(2 citation statements)

References 5 publications

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“…The neuroprotective effects of MTOR inhibitors could offer a new treatment approach for AMD, targeting shared pathways like oxidative stress that lead to retinal neuronal death (Armstrong et al, 2022). PLA2G7 is a key regulatory gene for understanding how adipose tissue metabolism influences immunometabolic responses (Candels et al, 2022). Rilapladib has demonstrated anti-inflammatory, antioxidant, and vascular-enhancing effects by targeting Phospholipase A2 (PLA2) and Platelet-activating factor acetylhydrolase (PLA2G7) in the treatment of Alzheimer’s disease (AD) (Maher-Edwards et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Multiomic Screening Unravels the Immunometabolic Signatures and Drug Targets of Age-Related Macular Degeneration

Cui,

Zhao,

Mahata

et al. 2024

Preprint

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Age-related macular degeneration (AMD) is a significant cause of visual impairment in the aging population, with the pathophysiology driven by a complex interplay of genetics, environmental influences and immunometabolic factors. These immunometabolic mechanisms, in particular, those distinguishing between the dry and wet forms of AMD, remain incompletely understood. Utilizing an integrated multiomic approach, incorporating Mendelian Randomization (MR) and single-cell RNA sequencing (scRNA-seq), we have effectively delineated distinct immunometabolic pathways implicated in the development of AMD. Our comprehensive analysis indicates that the androgen-IL10RA-CD16+ monocyte axis could protect against wet AMD. We have also identified several immune and metabolic signatures unique to each AMD subtype, with TNFα and Notch signaling pathways being central to disease progression. Furthermore, our analysis, leveraging expression Quantitative Trait Loci (eQTLs) from the Genotype-Tissue Expression (GTEx) project coupled with MR, have highlighted genes such as MTOR, PLA2G7, MAPKAPK3, ANGPTL1, and ARNT as prospective therapeutic targets. The therapeutic potential of these candidate genes was validated with observations from existing drug trial databases. Our robust genetic and transcriptomic approach has identified promising directions for novel AMD interventions, emphasizing the significance of an integrated multiomic approach in tackling this important cause of visual impairment.

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Section: Discussionmentioning

confidence: 99%

Multiomic Screening Unravels the Immunometabolic Signatures and Drug Targets of Age-Related Macular Degeneration

Cui,

Zhao,

Mahata

et al. 2024

Preprint

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“…P2RX1 is linked to the modulation of microbiota and the alleviation of inflammation in colitis [54]. PLA2G7, which is shown to be reduced in FOXO3 KO PMNs, is associated with inflammation [55]. Two other DEGs, MCAM and CDKN1A, in FOXO3 KO PMNs, are involved in tumorigenesis [56,57].…”

Section: Discussionmentioning

confidence: 99%

FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis

Ghimire

Iftikhar

Penrose

et al. 2023

IJMS

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Inflammatory bowel disease (IBD), characterized by infiltration of polymorphonuclear neutrophils (PMNs), increases the risk of colon cancer. PMN activation corresponds to the accumulation of intracellular Lipid Droplets (LDs). As increased LDs are negatively regulated by transcription factor Forkhead Box O3 (FOXO3), we aim to determine the significance of this regulatory network in PMN-mediated IBD and tumorigenesis. Affected tissue of IBD and colon cancer patients, colonic and infiltrated immune cells, have increased LDs’ coat protein, PLIN2. Mouse peritoneal PMNs with stimulated LDs and FOXO3 deficiency have elevated transmigratory activity. Transcriptomic analysis of these FOXO3-deficient PMNs showed differentially expressed genes (DEGs; FDR < 0.05) involved in metabolism, inflammation, and tumorigenesis. Upstream regulators of these DEGs, similar to colonic inflammation and dysplasia in mice, were linked to IBD and human colon cancer. Additionally, a transcriptional signature representing FOXO3-deficient PMNs (PMN-FOXO3389) separated transcriptomes of affected tissue in IBD (p = 0.00018) and colon cancer (p = 0.0037) from control. Increased PMN-FOXO3389 presence predicted colon cancer invasion (lymphovascular p = 0.015; vascular p = 0.046; perineural p = 0.03) and poor survival. Validated DEGs from PMN-FOXO3389 (P2RX1, MGLL, MCAM, CDKN1A, RALBP1, CCPG1, PLA2G7) are involved in metabolism, inflammation, and tumorigenesis (p < 0.05). These findings highlight the significance of LDs and FOXO3-mediated PMN functions that promote colonic pathobiology.

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Alzheimer’s Disease polygenic risk, the plasma proteome, and dementia incidence among UK older adults

Beydoun,

et al. 2024

GeroScience

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Alzheimer’s Disease (AD) is a complex polygenic neurodegenerative disorder. Its genetic risk’s relationship with all-cause dementia may be influenced by the plasma proteome. Up to 40,139 UK Biobank participants aged ≥ 50y at baseline assessment (2006–2010) were followed-up for ≤ 15 y for dementia incidence. Plasma proteomics were performed on a sub-sample of UK Biobank participants (k = 1,463 plasma proteins). AD polygenic risk scores (PRS) were used as the primary exposure and Cox proportional hazards models were conducted to examine the AD PRS-dementia relationship. A four-way decomposition model then partitioned the total effect (TE) of AD PRS on dementia into an effect due to mediation only, an effect due to interaction only, neither or both. The study found that AD PRS tertiles significantly increased the risk for all-cause dementia, particularly among women. The study specifically found that AD PRS was associated with a 79% higher risk for all-cause dementia for each unit increase (HR = 1.79, 95% CI: 1.70–1.87, P < 0.001). Eighty-six plasma proteins were significantly predicted by AD PRS, including a positive association with PLA2G7, BRK1, the glial acidic fibrillary protein (GFAP), neurofilament light chain (NfL), and negative with TREM2. Both GFAP and NfL significantly interacted synergistically with AD PRS to increase all-dementia risk (> 10% of TE is pure interaction), while GFAP was also an important consistent mediator in the AD PRS-dementia relationship. In summary, we detected significant interactions of NfL and GFAP with AD PRS, in relation to dementia incidence, suggesting potential for personalized dementia prevention and management.

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PLA2G7: a new player in shaping energy metabolism and lifespan

Cited by 3 publications

References 5 publications

Multiomic Screening Unravels the Immunometabolic Signatures and Drug Targets of Age-Related Macular Degeneration

Multiomic Screening Unravels the Immunometabolic Signatures and Drug Targets of Age-Related Macular Degeneration

FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis

Alzheimer’s Disease polygenic risk, the plasma proteome, and dementia incidence among UK older adults

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