Huq Tahrima Saiha, Luo Jean, Fakih Rayan, Sauvé Véronique, Gehring Kalle
Department of Biochemistry, McGill University, Montréal, Canada.
Centre de recherche en biologie structurale, McGill University, Montréal, Canada.
Commun Biol. 2024 Aug 8;7(1):961. doi: 10.1038/s42003-024-06656-x.
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Although most cases are sporadic and occur later in life, 10-15% of cases are genetic. Loss-of-function mutations in the ring-between-ring E3 ubiquitin ligase parkin, encoded by the PRKN gene, cause autosomal recessive forms of early onset PD. Together with the kinase PINK1, parkin forms a mitochondrial quality control pathway that tags damaged mitochondria for clearance. Under basal conditions, parkin is inhibited and compounds that increase its activity have been proposed as a therapy for PD. Recently, several naturally occurring hyperactive parkin variants were identified, which increased mitophagy in cultured cells. Here, we validate the hyperactivities of these variants in vitro and compare the levels of activity of the variants to those of the wild-type and the well-characterized hyperactive variant, W403A. We also study the effects of mutating the parkin ACT (activating element) on parkin activity in vitro. This work advances our understanding of the pathogenicity of parkin variants and is an important first step in the design of molecules to increase parkin activity.
帕金森病（PD）是世界上第二常见的神经退行性疾病。尽管大多数病例是散发性的且发生在晚年，但10%-15%的病例是遗传性的。由PRKN基因编码的环状E3泛素连接酶parkin中的功能丧失突变会导致早发性PD的常染色体隐性形式。Parkin与激酶PINK1一起形成线粒体质量控制途径，该途径标记受损线粒体以便清除。在基础条件下，parkin受到抑制，而增加其活性的化合物已被提议作为治疗PD的方法。最近，鉴定出了几种天然存在的高活性parkin变体，它们在培养细胞中增加了线粒体自噬。在这里，我们在体外验证了这些变体的高活性，并将变体的活性水平与野生型和特征明确的高活性变体W403A的活性水平进行了比较。我们还研究了在体外突变parkin ACT（激活元件）对parkin活性的影响。这项工作增进了我们对parkin变体致病性的理解，并且是设计增加parkin活性分子的重要第一步。
