Antoniou Nasia, Prodromidou Kanella, Kouroupi Georgia, Boumpoureka Ioanna, Samiotaki Martina, Panayotou George, Xilouri Maria, Kloukina Ismini, Stefanis Leonidas, Grailhe Regis, Taoufik Era, Matsas Rebecca
Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, 127 Vassilissis Sofias Avenue, 11521, Athens, Greece.
Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, Panepistimioupolis, Ilisia, Greece.
NPJ Parkinsons Dis. 2022 Feb 11;8(1):15. doi: 10.1038/s41531-022-00278-y.
Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease modeling represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson's disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the protective effects of BX795, comprising a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-αSyn in neuronal cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have identified a promising small molecule with neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.
将高通量筛选方法与基于诱导多能干细胞（iPSC）的疾病模型相结合，是一种很有前景的无偏倚策略，可用于识别神经退行性疾病的治疗方法。在此，我们对携带G209A（p.A53T）α-突触核蛋白（αSyn）突变的家族性帕金森病患者的iPSC衍生神经元进行了高内涵成像，并对一个小型激酶抑制剂文库开展了筛选活动。我们由此鉴定出多激酶抑制剂BX795，其单剂量就能有效恢复与疾病相关的神经退行性表型。蛋白质组学分析确定了BX795保护作用的分子途径，包括118种蛋白质介质，它们参与RNA代谢、蛋白质合成、修饰和清除以及应激反应等核心生物学过程，所有这些都与mTORC1信号枢纽相关。与此一致的是，神经元细胞中人类p.A53T-αSyn的表达影响了mTORC1途径的关键成分，导致异常蛋白质合成，而在存在BX795的情况下这种异常蛋白质合成得以恢复，同时自噬也得到促进。综上所述，我们已经鉴定出一种有前景的具有神经保护作用的小分子，作为帕金森病和其他蛋白质构象疾病的候选治疗药物。
