Investigation of ALS caused by mutant CHCHD10

肌萎缩性侧索硬化症（ALS）是一种多发病机制， 神经系统的病因和致命疾病，来自于对神经系统疾病的遗传基础的鉴定。 ALS病例的亚组。在ALS的该亚组（家族性ALS或FALS）中，该疾病作为家族性疾病遗传。 特质在所有ALS中确定单一的疾病机制一直是难以捉摸的，但值得注意的是， 提出的共同机制是线粒体功能障碍。然而，直到最近，没有直接的可靠的病因学 线粒体基因之间的联系，核或线粒体，已经发现。最近，其他人和我们发现， CHCHD 10基因的突变导致ALS和其他表型。一些其他的ALS基因， 包括VCP、HNRNPA 1、SQSTM 1和OPTN也与ALS以外的其他表型相关。 CHCHD 10及其蛋白产物尚未得到充分研究。为了研究CHCHD 10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基因等专业技能的人员 编辑，线粒体功能，氧化还原反应，诱导多能干细胞（iPSC）衍生的运动神经元 和初级运动神经元，在我的实验室和 合作者 我们将研究一种新的转基因小鼠模型的病理和行为， 过表达突变体（R15 L）人CHCHD 10基因。初步研究显示， 这只小鼠的脊髓和大脑具有周期性的珠状轴突鞘，其中含有线粒体。额外 还将开发更精确的模型。为了确定线粒体功能的哪个方面， 形态受到突变体CHCHD 10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。我们将鉴定CHCHD 10的结合蛋白伴侣 蛋白质，以了解CHCHD 10在线粒体生物学中的作用。研究完成后， 提供了对这种形式的ALS中的中心缺陷的更清楚的理解，并可能提供更细粒度的 理解线粒体缺陷在ALS中的普遍性。这项研究还将有助于确定 合理治疗和/或预防ALS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.