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Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood
Biological Psychiatry ( IF 10.6 ) Pub Date : 2022-11-09 , DOI: 10.1016/j.biopsych.2022.11.002
Yi-Jun Ge 1 , Ya-Nan Ou 1 , Yue-Ting Deng 2 , Bang-Sheng Wu 2 , Liu Yang 2 , Ya-Ru Zhang 2 , Shi-Dong Chen 2 , Yu-Yuan Huang 2 , Qiang Dong 2 , Lan Tan 1 , Jin-Tai Yu 2 ,
Affiliation  

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 Alzheimer’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. Interventions 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 targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain.

Conclusions

Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets.



中文翻译:

通过整合来自大脑和血液的遗传和蛋白质组学数据确定神经退行性疾病药物靶标的优先级

背景

神经退行性疾病是最普遍和最具破坏性的神经系统疾病之一,几乎没有有效的预防和治疗策略。我们的目标是整合遗传和蛋白质组学数据,以优先考虑神经退行性疾病的药物靶点。

方法

我们通过孟德尔随机化筛选人类蛋白质组,以确定阿尔茨海默病、帕金森病、肌萎缩侧索硬化、多发性硬化、额颞叶痴呆和路易体痴呆的致病介质。对于仪器,我们使用分别从一项涉及 376 名参与者的全基因组关联研究和另一项涉及 3301 名参与者的研究中确定的大脑和血液蛋白质数量性状位点。随后通过敏感性分析和共定位验证了因果关系。还评估了已确定目标的安全性和成药性。

结果

我们的分析表明,靶向血液中的 BIN1、GRN 和 RET 水平以及大脑中的 ACE、ICA1L、MAP1S、SLC20A2 和 TOM1L2 水平可能会降低阿尔茨海默病风险,而 ICA1L、SLC20A2 和 TOM1L2 不推荐作为优先药物,因为确定的潜在副作用。脑 CD38、DGKQ、GPNMB 和 SEC23IP 是帕金森病的候选靶点。其中,GPNMB 是帕金森病最有希望的靶标,其因果关系已通过对大脑和血液组织的研究得到证实。针对血液中的 FCRL3、LMAN2 和 MAPK3 以及大脑中的 DHRS11、FAM120B、SHMT1 和 TSFM 的干预措施可能会影响多发性硬化症的风险。针对大脑中的 DHRS11、PSMB3、SARM1 和 SCFD1 的药物可能会降低肌萎缩侧索硬化的风险。

结论

我们的研究优先将 22 种蛋白质作为神经退行性疾病的靶标,并为药物开发提供了初步证据。需要进一步的研究来验证这些目标。

更新日期:2022-11-09
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