Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood

BACKGROUND: Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. METHODS: We screened human proteomes through Mendelian randomization to identify causal mediators of Alz-heimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. RESULTS: Our analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimer's disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinson's disease. Among them, GPNMB was the most promising target for Parkinson's disease with their causal relationship evidenced by studies on both brain and blood tissues. In-terventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications tar-geting DHRS11, PSMB3, SARM1, and SCFD1 in brain. CONCLUSIONS: Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided pre-liminary evidence for drug development. Further studies are warranted to validate these targets.

Automated summary

In this study, genetic and proteomic data were integrated to prioritize drug targets for neurodegenerative diseases. The analysis identified several proteins as potential targets for different diseases, such as BIN1, GRN, RET, CD38, DGKQ, GPNMB, FCRL3, LMAN2, MAPK3, DHRS11, FAM120B, SHMT1, PSMB3, SARM1, and SCFD1.