Objective: To assess the causal impact of plasma Cathepsin B (CTSB) levels on Parkinson’s disease (PD) risk.

Background: Cathepsin B is a crucial lysosomal cysteine protease involved in proenzyme activation and protein degradation. Dysfunction of lysosomal proteases, including CTSB, has been implicated in PD pathogenesis. While genetic studies have suggested that variants in the CTSB gene may influence PD risk, the causal relationship between plasma CTSB levels and PD remains unclear.

Method: This study employed a two-sample Mendelian randomization (MR) approach to investigate the causal association between plasma CTSB levels and PD. Summary-level data for plasma CTSB levels and PD risk were obtained from OpenGWAS and were analyzed using the TwoSampleMR [1, 2]. Four independent single-nucleotide polymorphisms (SNPs) associated with CTSB levels (P<1E-06) were used as instrumental variables. The inverse variance weighted (IVW) analysis was applied as the primary method to calculate causal estimates. Sensitivity analyses, along with pleiotropy and heterogeneity tests, were conducted to evaluate the robustness of the results.

Results: The IVW analysis revealed that higher plasma CTSB levels were causally associated with a reduced risk of PD (OR=0.86, 95%CI=0.78-0.95, P=0.004). Additional MR methods supported this finding, yielding consistent results with the same protective trend. No evidence of horizontal pleiotropy or significant heterogeneity was detected, as indicated by the MR-Egger test and Cochran’s Q test (P>0.05), confirming the reliability of the results.

Conclusion: This MR study suggests that elevated plasma CTSB levels are causally linked to a decreased risk of PD, highlighting CTSB as a potential biomarker and therapeutic target for PD.

Figure 1

References: 1. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, Tan M, Kia DA, Noyce AJ, Xue A: Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. The Lancet Neurology 2019, 18(12):1091-1102.
2. Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, Burgess S, Jiang T, Paige E, Surendran P et al: Genomic atlas of the human plasma proteome. Nature 2018, 558(7708):73-79.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/blood-levels-of-cathepsin-b-are-linked-to-a-reduced-risk-of-parkinsons-disease/