Investigation of ALS caused by mutant CHCHD10

在对肌萎缩侧索硬化症(ALS)的认识方面取得了一些最有力的进展，ALS是一种多因素的疾病。 神经系统的病因和致命性疾病，都来自于对一种 肌萎缩侧索硬化症病例亚群。在ALS(家族性ALS或FALS)的这个亚群中，这种疾病是作为家族性遗传的 特质。所有肌萎缩侧索硬化症的单一发病机制一直难以确定，但值得注意的是 提出的常见机制是线粒体功能障碍。然而，直到最近，还没有直接可靠的病因学 线粒体基因之间的联系，核或线粒体，已被发现。最近，其他人和我们发现 一种名为CHCHD10的基因突变会导致ALS和其他表型。其他一些肌萎缩侧索硬化基因， 除ALS外，VCP、HNRNPA1、SQSTM1和OPTN也与其他表型相关。 目前对CHCHD10及其蛋白产物的研究还不够深入。为了研究CHCHD10的突变如何导致 ALS，我们已经收集或开发了有前途的试剂，并组装了合作者和实验室 具有基因工程、啮齿动物模型、细胞生物学、CRISPR/Cas9基因方面专门技能的人员 编辑，线粒体功能，氧化还原反应，诱导多能干细胞(IPSC)来源的运动神经元 和初级运动神经元在我的实验室和 合作者。 我们将研究我们设计的一种新的转基因小鼠模型的病理学和行为 高效表达突变型(R15L)人CHCHD10基因。初步研究显示轴突病理改变 这种小鼠的脊髓和大脑，有周期性的串珠状轴突肿胀，内含线粒体。其他内容 还将开发更精确的模型。以确定线粒体功能的哪个方面或 形态受突变体CHCHD10的影响我们将筛选线粒体功能的能量学，氧化还原研究， 钙缓冲和电子显微镜分析。我们将确定CHCHD10的结合蛋白伙伴(S) 了解CHCHD10在线粒体生物学中的作用。完成后，我们的研究将 提供对这种形式的肌萎缩侧索硬化症的中心缺陷(S)的更清晰的理解，并潜在地提供更细粒的 对肌萎缩侧索硬化症中可概括的线粒体缺陷的理解。这项研究还将允许确定 ALS的合理治疗和/或预防的潜在分子靶点。

Some of the most robust advances in the understanding of amyotrophic lateral sclerosis (ALS), a multi- etiologic and fatal disorder of the nervous system, have come from the identification of the genetic basis of a subgroup of ALS cases. In this subgroup of ALS (familial ALS or FALS), the disease is inherited as a familial trait. Identification of a single mechanism of disease across all of ALS has been elusive, but notable amongst proposed common mechanisms is mitochondrial dysfunction. However, till recently, no direct robust etiological link between mitochondrial genes, nuclear or mitochondrial, had been found. Recently, others and we found that mutations in a gene called CHCHD10 causes ALS and additional phenotypes. Some other ALS genes, including VCP, HNRNPA1, SQSTM1 and OPTN are also associated with other phenotypes besides ALS. CHCHD10 and its protein product are not well studied. To investigate how a mutation in CHCHD10 may cause ALS, we have collected or developed promising reagents and assembled collaborators and laboratory personnel with specialized skills in genetic engineering, rodent models, cell biology, CRISPR/Cas9 gene editing, mitochondrial function, redox response, induced pluripotent stem cell (iPSC) derived motor neurons and primary motor neurons to carry out the proposed experiments in my laboratory and the laboratories of collaborators. We will investigate the pathology and behavior of a new transgenic mouse model we have engineered to overexpress the mutant (R15L) human CHCHD10 gene. Preliminary study shows axonal pathology in the spinal cord and brain of this mouse with periodic beaded axonal swellings harboring mitochondria. Additional more precise models will also be developed. To determine what aspect of mitochondrial function or morphology is affected by mutant CHCHD10 we will screen mitochondrial function of energetics, redox studies, calcium buffering and electron microscopy analysis. We will identify the binding protein partner(s) of CHCHD10 protein to understand the role of CHCHD10 in the mitochondrial biology. On completion, our study would provide a clearer understanding of the central defect(s) in this form of ALS and potentially a more granular understanding of mitochondrial defect generalizable across ALS. The study will also allow the identification of potential molecular targets for rational therapy and/or prevention of ALS.