Genetic Insights Into the Role of Cathepsins in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis: Evidence From Mendelian Randomization Study

Overview

Journal Brain Behav

Specialty Psychology

Date 2024 Dec 31

PMID 39740768

Authors

Yanhong Jiang

Wenhui Fan

Yaxin Li

Hua Xue

Affiliations

Soon will be listed here.

Abstract

Background: Previous studies have confirmed the significant role of cathepsins in the development of neurodegenerative diseases. We aimed to determine whether genetically predicted 10 cathepsins may have a causal effect on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

Methods: We conducted a two-sample bidirectional Mendelian randomization (MR) study using publicly available data from genome-wide association study (GWAS) to assess the causal associations between 10 cathepsins and three neurodegenerative diseases, including AD, PD, and ALS. We employed the following methods, including inverse variance weighting (IVW), MR-Egger, and weighted median (WM). The results were further validated using sensitivity analysis.

Results: The forward MR analysis results indicate that elevated cathepsin H levels increase the risk of AD (p = 0.005, odds ratio [OR] = 1.040, 95% confidence interval [CI] = 1.011-1.069), elevated cathepsin B levels decrease the risk of PD (p < 0.001, OR = 0.890, 95% CI = 0.831-0.954), and no significant association was found between cathepsin levels and ALS. Reverse MR analysis suggests that there is no causal association between 10 cathepsins and three neurodegenerative diseases.

Conclusion: Our study provides new genetic insights into the role of cathepsin H in AD and cathepsin B in PD. However, our findings need to be further validated in a wider population, and future research should explore the potential mechanisms of cathepsins in these diseases in order to provide a basis for the development of new therapeutic strategies.

References

Bowden J, Davey Smith G, Haycock P, Burgess S . Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016; 40(4):304-14. PMC: 4849733. DOI: 10.1002/gepi.21965. View

Bouras E, Karhunen V, Gill D, Huang J, Haycock P, Gunter M . Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis. BMC Med. 2022; 20(1):3. PMC: 8750876. DOI: 10.1186/s12916-021-02193-0. View

McGlinchey R, Lee J . Cysteine cathepsins are essential in lysosomal degradation of α-synuclein. Proc Natl Acad Sci U S A. 2015; 112(30):9322-7. PMC: 4522768. DOI: 10.1073/pnas.1500937112. View

Wang T, Ni Q, Wang K, Han Z, Sun B . Stroke and Alzheimer's Disease: A Mendelian Randomization Study. Front Genet. 2020; 11:581. PMC: 7371994. DOI: 10.3389/fgene.2020.00581. View

Yusufujiang A, Zeng S, Li H . Cathepsins and Parkinson's disease: insights from Mendelian randomization analyses. Front Aging Neurosci. 2024; 16:1380483. PMC: 11188310. DOI: 10.3389/fnagi.2024.1380483. View

Tran A, Silver J . Cathepsins in neuronal plasticity. Neural Regen Res. 2020; 16(1):26-35. PMC: 7818855. DOI: 10.4103/1673-5374.286948. View

Chang D, Nalls M, Hallgrimsdottir I, Hunkapiller J, van der Brug M, Cai F . A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci. Nat Genet. 2017; 49(10):1511-1516. PMC: 5812477. DOI: 10.1038/ng.3955. View

Offen D, Barhum Y, Melamed E, Embacher N, Schindler C, Ransmayr G . Spinal cord mRNA profile in patients with ALS: comparison with transgenic mice expressing the human SOD-1 mutant. J Mol Neurosci. 2008; 38(2):85-93. DOI: 10.1007/s12031-007-9004-z. View

Wootz H, Weber E, Korhonen L, Lindholm D . Altered distribution and levels of cathepsinD and cystatins in amyotrophic lateral sclerosis transgenic mice: possible roles in motor neuron survival. Neuroscience. 2006; 143(2):419-30. DOI: 10.1016/j.neuroscience.2006.07.048. View

10.

Liu X, Ou Y, Ma Y, Huang L, Zhang W, Tan L . Renal function and neurodegenerative diseases : a two-sample Mendelian randomization study. Neurol Res. 2023; 45(5):456-464. DOI: 10.1080/01616412.2022.2158640. View

11.

Li J, Tang M, Gao X, Tian S, Liu W . Mendelian randomization analyses explore the relationship between cathepsins and lung cancer. Commun Biol. 2023; 6(1):1019. PMC: 10560205. DOI: 10.1038/s42003-023-05408-7. View

12.

Bellenguez C, Kucukali F, Jansen I, Kleineidam L, Moreno-Grau S, Amin N . New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022; 54(4):412-436. PMC: 9005347. DOI: 10.1038/s41588-022-01024-z. View

13.

Nasir A, Ur Rehman M, Khan T, Husn M, Khan M, Khan A . Advances in nanotechnology-assisted photodynamic therapy for neurological disorders: a comprehensive review. Artif Cells Nanomed Biotechnol. 2024; 52(1):84-103. DOI: 10.1080/21691401.2024.2304814. View

14.

Howie A, Burnett D, Crocker J . The distribution of cathepsin B in human tissues. J Pathol. 1985; 145(4):307-14. DOI: 10.1002/path.1711450404. View

15.

Wendt W, Lubbert H, Stichel C . Upregulation of cathepsin S in the aging and pathological nervous system of mice. Brain Res. 2008; 1232:7-20. DOI: 10.1016/j.brainres.2008.07.067. View

16.

Tsujimura A, Taguchi K, Watanabe Y, Tatebe H, Tokuda T, Mizuno T . Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils. Neurobiol Dis. 2014; 73:244-53. DOI: 10.1016/j.nbd.2014.10.011. View

17.

Lecaille F, Chazeirat T, Saidi A, Lalmanach G . Cathepsin V: Molecular characteristics and significance in health and disease. Mol Aspects Med. 2022; 88:101086. DOI: 10.1016/j.mam.2022.101086. View

18.

Li C, Liu J, Lin J, Shang H . COVID-19 and risk of neurodegenerative disorders: A Mendelian randomization study. Transl Psychiatry. 2022; 12(1):283. PMC: 9281279. DOI: 10.1038/s41398-022-02052-3. View

19.

Ni J, Wu Z, Stoka V, Meng J, Hayashi Y, Peters C . Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice. Aging Cell. 2018; 18(1):e12856. PMC: 6351837. DOI: 10.1111/acel.12856. View

20.

Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z . Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes. Science. 2019; 365(6450). PMC: 6658218. DOI: 10.1126/science.aav9518. View