Hertz Nicholas, Chin Randall, Rakhit Rishi, Ditsworth Dara, Wang Chengzhong, Bartholomeus Johan, Liu Song, Mody Akash, Laihsu Alex, Eastes Andrea, Tai Chao, Kim Roy, Li Jessica, Khasnavis Saurabh, Rafalski Victoria, Heerendeen Donald, Garda Virginia, Phung Jennie, de Roulet Daniel, Ordureau Alban, Harper J Wade, Johnstone Shawn, Stöhr Jan
Mitokinin Inc.
Gladstone Institutes/UCSF.
Res Sq. 2024 May 10:rs.3.rs-4356493. doi: 10.21203/rs.3.rs-4356493/v1.
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.
PINK1功能丧失突变和接触线粒体毒素分别是帕金森病（PD）和帕金森综合征的病因。我们证明，病理性α-突触核蛋白沉积是特发性PD的标志性病理特征，它会诱导线粒体功能障碍，并损害线粒体自噬，这可通过PINK1底物pS65-泛素（pUb）的积累得到证明。我们发现了MTK458，一种可穿透血脑屏障的小分子，它与PINK1结合并稳定其活性复合物，从而提高线粒体自噬速率。在体外和体内的α-突触核蛋白病理模型中，用MTK458治疗可介导清除积累的pUb和α-突触核蛋白病理特征。我们在临床前PD模型中的研究结果表明，PINK1的药理学激活作为PD疾病修饰的治疗策略值得进一步临床评估。
