Genome-Wide Mendelian Randomization Identifies Ferroptosis-Related Drug Targets for Alzheimer's Disease

Overview

Journal J Alzheimers Dis Rep

Publisher IOS Press

Date 2024 Sep 9

PMID 39247875

Authors

Ying Wang

Xinhua Song

Rui Wang

Xinzi Xu

Yaming Du

Guohua Chen

Junhua Mei

Affiliations

Soon will be listed here.

Abstract

Background: Alzheimer's disease (AD) currently lacks effective disease-modifying treatments. Recent research suggests that ferroptosis could be a potential therapeutic target. Mendelian randomization (MR) is a widely used method for identifying novel therapeutic targets.

Objective: Employ genetic information to evaluate the causal impact of ferroptosis-related genes on the risk of AD.

Methods: 564 ferroptosis-related genes were obtained from FerrDb. We derived genetic instrumental variables for these genes using four brain quantitative trait loci (QTL) and two blood QTL datasets. Summary-data-based Mendelian randomization (SMR) and two-sample MR methods were applied to estimate the causal effects of ferroptosis-related genes on AD. Using extern transcriptomic datasets and triple-transgenic mouse model of AD (3xTg-AD) to further validate the gene targets identified by the MR analysis.

Results: We identified 17 potential AD risk gene targets from GTEx, 13 from PsychENCODE, and 22 from BrainMeta (SMR < 0.05 and HEIDI test > 0.05). Six overlapping ferroptosis-related genes associated with AD were identified, which could serve as potential therapeutic targets and ). Additionally, we further pinpointed risk genes or proteins at the blood tissue and pQTL levels. Notably, demonstrated significant dysregulation in the extern transcriptomic datasets and 3xTg-AD models.

Conclusions: This study provides genetic evidence supporting the potential therapeutic benefits of targeting the six druggable genes for AD treatment, especially for (validated by transcriptome and 3xTg-AD), which could be useful for prioritizing AD drug development in the field of ferroptosis.

References

Wang P, Zou F, Zhang X, Li H, Dulak A, Tomko Jr R . microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Cancer Res. 2009; 69(20):8157-65. PMC: 2763324. DOI: 10.1158/0008-5472.CAN-09-1996. View

Choi H, Jeong Y, Kim J, Hoe H . EGFR is a potential dual molecular target for cancer and Alzheimer's disease. Front Pharmacol. 2023; 14:1238639. PMC: 10433764. DOI: 10.3389/fphar.2023.1238639. View

Bahar M, Kim H, Kim D . Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther. 2023; 8(1):455. PMC: 10725898. DOI: 10.1038/s41392-023-01705-z. View

Wakatsuki S, Furuno A, Ohshima M, Araki T . Oxidative stress-dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration. J Cell Biol. 2015; 211(4):881-96. PMC: 4657170. DOI: 10.1083/jcb.201506102. View

Ma H, Dong Y, Chu Y, Guo Y, Li L . The mechanisms of ferroptosis and its role in alzheimer's disease. Front Mol Biosci. 2022; 9:965064. PMC: 9459389. DOI: 10.3389/fmolb.2022.965064. View

Hambright W, Fonseca R, Chen L, Na R, Ran Q . Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017; 12:8-17. PMC: 5312549. DOI: 10.1016/j.redox.2017.01.021. View

Wang B, Zhang J, Song F, Tian M, Shi B, Jiang H . EGFR regulates iron homeostasis to promote cancer growth through redistribution of transferrin receptor 1. Cancer Lett. 2016; 381(2):331-40. DOI: 10.1016/j.canlet.2016.08.006. View

Jakaria M, Belaidi A, Bush A, Ayton S . Ferroptosis as a mechanism of neurodegeneration in Alzheimer's disease. J Neurochem. 2021; 159(5):804-825. DOI: 10.1111/jnc.15519. View

Zhang G, Fang Y, Li X, Zhang Z . Ferroptosis: A novel therapeutic strategy and mechanism of action in glioma. Front Oncol. 2022; 12:947530. PMC: 9520297. DOI: 10.3389/fonc.2022.947530. View

10.

Ye L, Wen X, Qin J, Zhang X, Wang Y, Wang Z . Metabolism-regulated ferroptosis in cancer progression and therapy. Cell Death Dis. 2024; 15(3):196. PMC: 10923903. DOI: 10.1038/s41419-024-06584-y. View

11.

Auton A, Brooks L, Durbin R, Garrison E, Kang H, Korbel J . A global reference for human genetic variation. Nature. 2015; 526(7571):68-74. PMC: 4750478. DOI: 10.1038/nature15393. View

12.

Ghoussaini M, Nelson M, Dunham I . Future prospects for human genetics and genomics in drug discovery. Curr Opin Struct Biol. 2023; 80:102568. PMC: 7614359. DOI: 10.1016/j.sbi.2023.102568. View

13.

Stefanovska B, Andre F, Fromigue O . Tribbles Pseudokinase 3 Regulation and Contribution to Cancer. Cancers (Basel). 2021; 13(8). PMC: 8070086. DOI: 10.3390/cancers13081822. View

14.

McKay E, Beck J, Khoo S, Dykema K, Cottingham S, Winn M . Peri-Infarct Upregulation of the Oxytocin Receptor in Vascular Dementia. J Neuropathol Exp Neurol. 2019; 78(5):436-452. PMC: 6467199. DOI: 10.1093/jnen/nlz023. View

15.

Vitalakumar D, Sharma A, Flora S . Ferroptosis: A potential therapeutic target for neurodegenerative diseases. J Biochem Mol Toxicol. 2021; 35(8):e22830. DOI: 10.1002/jbt.22830. View

16.

Chen Y, Hsu C, Shiao Y, Wang H, Lo Y, Lin A . Anti-inflammatory effect of afatinib (an EGFR-TKI) on OGD-induced neuroinflammation. Sci Rep. 2019; 9(1):2516. PMC: 6385176. DOI: 10.1038/s41598-019-38676-7. View

17.

Zhu Z, Zhang F, Hu H, Bakshi A, Robinson M, Powell J . Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016; 48(5):481-7. DOI: 10.1038/ng.3538. View

18.

Plascencia-Villa G, Perry G . Preventive and Therapeutic Strategies in Alzheimer's Disease: Focus on Oxidative Stress, Redox Metals, and Ferroptosis. Antioxid Redox Signal. 2020; 34(8):591-610. PMC: 8098758. DOI: 10.1089/ars.2020.8134. View

19.

Oddo S, Caccamo A, Kitazawa M, Tseng B, LaFerla F . Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging. 2003; 24(8):1063-70. DOI: 10.1016/j.neurobiolaging.2003.08.012. View

20.

Hao X, Wang H, Cui F, Yang Z, Ye L, Huang R . Reduction of SLC7A11 and GPX4 Contributing to Ferroptosis in Sperm from Asthenozoospermia Individuals. Reprod Sci. 2022; 30(1):247-257. DOI: 10.1007/s43032-022-01004-y. View