Homeostatic p62 levels and inclusion body formation in CHCHD2 knockout mice
Homeostatic p62 levels and inclusion body formation in CHCHD2 knockout mice
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DOI：
10.1093/hmg/ddab057
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发表时间：
2021-02-25
影响因子：
3.5
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
--
作者：
Sato, Shigeto;Noda, Sachiko;Hattori, Nobutaka
组成性自噬失活导致神经元中细胞质内含物的形成，但受损的自噬与路易体（LB）之间的关系仍然未知。α-突触核蛋白和p62是LB的成分，是帕金森病（PD）的定义特征。到目前为止，我们已经分析了小鼠模型，并证明来自自噬缺陷的p62聚集体可能作为“种子”，并可能是LB形成的原因。P62可能是聚集体形成的关键分子。为了了解LB的机制，我们使用PD模型小鼠分析了p62稳态和包涵体形成。在PARK 22相关的PD中，内在无序的突变CHCHD 2启动Lewy病理。为了确定CHCHD 2对包涵体形成的功能，我们产生了Chchd 2敲除（KO）小鼠，并表征了年龄相关的病理和运动表型。Chchd 2 KO小鼠表现出p62包涵体形成和多巴胺能神经元损失的年龄依赖性方式。这些变化与线粒体复合物活性降低和线粒体内部结构的废除有关。特别是，OPA 1蛋白，调节线粒体内膜的融合，是不成熟的CHCHD 2缺陷小鼠的线粒体。CHCHD 2通过控制OPA 1的水平来调节线粒体形态和p62稳态。我们的研究结果强调了p62的稳态水平在控制细胞内包涵体形成中的意想不到的作用，p62由非自噬系统调节，并表明与线粒体蛋白水解系统相关的病理过程对DA神经元的丧失至关重要。
Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurones, but the relationship between impaired autophagy and Lewy bodies (LBs) remains unknown. a-Synuclein and p62, components of LBs, are the defining characteristic of Parkinson's disease (PD). Until now, we have analyzed mice models and demonstrated p62 aggregates derived from an autophagic defect might serve as `seeds' and can potentially be a cause of LB formation. P62 may be the key molecule for aggregate formation. To understand the mechanisms of LBs, we analyzed p62 homeostasis and inclusion formation using PD model mice. In PARK22-linked PD, intrinsically disordered mutant CHCHD2 initiates Lewy pathology. To determine the function of CHCHD2 for inclusions formation, we generated Chchd2-knockout (KO) mice and characterized the age-related pathological and motor phenotypes. Chchd2 KO mice exhibited p62 inclusion formation and dopaminergic neuronal loss in an age-dependent manner. These changes were associated with a reduction in mitochondria complex activity and abrogation of inner mitochondria structure. In particular, the OPA1 proteins, which regulate fusion of mitochondrial inner membranes, were immature in the mitochondria of CHCHD2-deficient mice. CHCHD2 regulates mitochondrial morphology and p62 homeostasis by controlling the level of OPA1. Our findings highlight the unexpected role of the homeostatic level of p62, which is regulated by a non-autophagic system, in controlling intracellular inclusion body formation, and indicate that the pathologic processes associated with the mitochondrial proteolytic system are crucial for loss of DA neurones.Y