Integrated Genomic, Proteomic, and Transcriptomic Profiling Support Cathepsin-B as a Drug Repurposing Target in Cerebral Small Vessel Disease
Cyprien Rivier1, Shufan Huo1, Santiago Clocchiatti-Tuozzo2, Daniela Renedo1, Richa Sharma3, Sam Payabvash2, Srikant Rangaraju4, Xianjun Dong2, Kevin Sheth5, Lauren Sansing6, Guido Falcone7
1Yale University, 2Yale University, Department of Neurology, 3Massachusetts General Hospital, Brigham, Harvard, 4Emory University, Atlanta, 5Yale UniversityDivision of Neuro and Critical Care, 6yale University, Department of Neurology, 7Yale School of Medicine
Objective:
Integrate genomic, proteomic, and transcriptomic data to identify proteins that may target and slow the progression of White Matter Hyperintensities (WMH).
Background:
WMH, a radiographic indicator of Cerebral Small Vessel Disease (CSVD) and a determinant of stroke and dementia, currently lacks specific drug targets. Particularly promising are proteins serving as pathway-level hubs through which polygenic effects converge.
Design/Methods:
We analyzed data from 53,014 UK Biobank participants using the following pipeline: 1)association analyses between a polygenic risk score of WMH and 2,923 protein levels; 2)evaluation of proteins selected in step 1 for association with WMH volume, ascertained through research MRIs; 3)mediation analyses to confirm that proteins with significant and directionally concordant associations with both the polygenic score and WMH are indeed mediators of the polygenic score-WMH relationship; 4)Mendelian Randomization using cis-protein quantitative trait loci to evaluate causality between selected proteins and WMH and other CSVD traits. Additionally, differential expression was examined in single-nucleus RNA sequencing from WMH lesions in four vascular dementia patients and four controls.
Results:
Cathepsin B (CTSB) was the sole protein meeting all the criteria. Mendelian Randomization confirmed CTSB’s association with WMH (β:−0.092, SE:0.003, P<0.001) and other CSVD traits: intracerebral hemorrhage, small vessel stroke, perivascular space volume, and white matter microstructure changes. In alignment with CTSB’s protective effect on CSVD, CTSB expression was significantly reduced in astrocytes (log₂FC:−1.7, adj.p<0.0001), oligodendrocytes (log₂FC:−0.48, adj.p<0.0001), and microglia (log₂FC:−0.35, adj.p<0.0001) of WMH lesions compared to healthy white matter.
Conclusions:
Our combined multi-omics approach identified CTSB as a protein protective for WMH and other CSVD phenotypes. CTSB, a lysosomal protease involved in the autophagy-lysosomal pathway is well-known for its involvement in hypoxia/ischemia-induced neuronal death, a key mechanism leading to WMH. Compounds targeting CTSB have shown promise in reducing neuronal death in Alzheimer’s models, suggesting potential for repurposing to stabilize WMH and reduce subsequent stroke and dementia risk.
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