Certara QSP, Breda, The Netherlands.
Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
CPT Pharmacometrics Syst Pharmacol. 2019 Feb;8(2):77-86. doi: 10.1002/psp4.12362. Epub 2018 Nov 2.
Parkinsons disease (PD) is a progressive neurodegenerative disease with substantial and growing socio-economic burden. In this multifactorial disease, aging, environmental, and genetic factors contribute to neurodegeneration and dopamine (DA) deficiency in the brain. Treatments aimed at DA restoration provide symptomatic relief, however, no disease modifying treatments are available, and PD remains incurable to date. Mathematical modeling can help understand such complex multifactorial neurological diseases. We review mathematical modeling efforts in PD with a focus on mechanistic models of pathogenic processes. We consider models of α-synuclein (Asyn) aggregation, feedbacks among Asyn, DA, and mitochondria and proteolytic systems, as well as pathology propagation through the brain. We hope that critical understanding of existing literature will pave the way to the development of quantitative systems pharmacology models to aid PD drug discovery and development.
帕金森病（PD）是一种进行性神经退行性疾病，具有巨大且不断增长的社会经济负担。在这种多因素疾病中，衰老、环境和遗传因素导致大脑中的神经退行性变和多巴胺（DA）缺乏。旨在恢复 DA 的治疗方法提供了症状缓解，但目前尚无疾病修饰治疗方法，PD 仍然无法治愈。数学建模可以帮助理解这种复杂的多因素神经疾病。我们回顾了 PD 的数学建模工作，重点是发病机制的机制模型。我们考虑了α-突触核蛋白（Asyn）聚集、Asyn、DA 和线粒体与蛋白水解系统之间的反馈，以及通过大脑传播的病理学。我们希望对现有文献的批判性理解将为开发定量系统药理学模型铺平道路，以帮助 PD 药物发现和开发。
