药理激活 PINK1 可改善帕金森病模型的病理变化

Nicholas Hertz, Randall Chin, Rishi Rakhit, D. Ditsworth, Chengzhong Wang, Johan Bartholomeus, Song Liu, Akash Mody, Alex Laihsu, A. Eastes, Chao Tai, Roy Kim, Jessica Li, Saurabh Khasnavis, Victoria Rafalski, Donald Heerendeen, Virginia Garda, Jennie Phung, Daniel de Roulet, A. Ordureau, J. W. Harper, Shawn Johnstone, Jan Stöhr
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引用次数: 0

摘要

摘要 PINK1功能缺失突变和线粒体毒素暴露分别是帕金森病(PD)和帕金森综合症的致病原因。我们证明,病理性α-突触核蛋白沉积是特发性帕金森病的标志性病理特征,会诱发线粒体功能障碍,并损害有丝分裂,PINK1底物pS65-泛素(pUb)的积累就是证明。我们发现了一种脑穿透性小分子 MTK458,它能与 PINK1 结合并稳定其活性复合物,从而提高有丝分裂率。在体外和体内的α-突触核蛋白病理模型中,用MTK458治疗可介导累积的pUb和α-突触核蛋白病理的清除。我们从临床前帕金森病模型中获得的研究结果表明,药理激活 PINK1 作为帕金森病的一种治疗策略,值得进一步进行临床评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models
Abstract PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson’s disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction, and impairs mitophagy as evidenced by the accumulation of the PINK1 substrate pS65-Ubiquitin (pUb). We discovered MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes its active complex, resulting in increased rates of mitophagy. Treatment with MTK458 mediates clearance of accumulated pUb and α-synuclein pathology in α-synuclein pathology models in vitro and in vivo. Our findings from preclinical PD models suggest that pharmacological activation of PINK1 warrants further clinical evaluation as a therapeutic strategy for disease modification in PD.
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