Autophagy activating drug repurposing based on context-specific network for Parkinson’s disease

Background: Parkinson's disease (PD) is a major long-term degenerative disease that affects the motor system. Parkinson's disease has been increasing over the past 30 years, despite ongoing research and efforts at drug development. The reason is that previous drug development for Parkinson's disease has mainly focused on recovering dopamine levels, which only provides short-term relief. The treatment of PD requires a fundamental approach to treatment. Recent studies prove that misfolded protein aggregation causes mitochondria dysfunction and neuroinflammation so the elimination of the misfolded protein should offer an effective long-term treatment for Parkinson's disease. A promising mechanism to eliminate the misfolded protein is autophagy. Results: We developed a pipeline to identify autophagy-inducing candidate drugs for Parkinson's disease based on Parkinson's disease-specific network and the relationship between drug targets and core autophagy genes. We found 3 autophagy-related genes using RWR algorithm and six drug-repurposing candidates to PD. Conclusions: Our drug repurposing pipeline provides that candidate drugs that show a notable possibility for fundamental PD treatment by activating the autophagy mechanism.

背景：帕金森病（Parkinson's disease, PD）是一类主要累及运动系统的慢性退行性疾病。尽管相关研究与药物开发工作持续推进，过去30年间帕金森病的患病率仍持续攀升。既往帕金森病药物研发多聚焦于恢复多巴胺水平，但仅能实现短期症状缓解。帕金森病的治疗亟需根本性的治疗策略。近期研究证实，错误折叠蛋白聚集会引发线粒体功能障碍与神经炎症，因此清除错误折叠蛋白有望为帕金森病提供有效的长期治疗方案。清除错误折叠蛋白的极具前景的机制之一是自噬（autophagy）。
结果：本研究基于帕金森病特异性调控网络以及药物靶点与核心自噬基因的关联关系，构建了用于筛选可诱导自噬的帕金森病候选药物的分析流程。通过随机游走重启（Random Walk with Restart, RWR）算法筛选得到3个自噬相关基因，并获得6款针对帕金森病的药物重定位候选药物。
结论：本研究构建的药物重定位分析流程表明，所筛选出的候选药物可通过激活自噬机制，为帕金森病的根本性治疗提供极具潜力的应用前景。