Neurodegenerative Mechanisms in Christianson Syndrome and NHE6-Related Disorders

Christianson 综合征和 NHE6 相关疾病的神经退行性机制

基本信息

批准号：
10653694
负责人：
Eric M Morrow
金额：
$ 71.89万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653694
关键词：
Address Adult Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Axonal Transport Biochemical Brain Cells Cellular biology Cerebellar degeneration Christianson syndrome Collection Communities Data Defect Development Developmental Delay Disorders Diffuse Disease Early Endosome Endosomes Epilepsy Exhibits Exons Experimental Models Female Functional disorder GTPase-Activating Proteins Genes Genetic Diseases Heterozygote Human Human Genetics Impairment In Vitro International Laboratories Lead Lighting Link Lysosomes Mediating Microscopy Modeling Mus Mutation Natural History Nerve Degeneration Neurodegenerative Disorders Neurons Pathologic Pathology Patients Phenotype Population Positioning Attribute Public Health Publishing Rattus Research Resources Role Site Sorting Speed Structure Synapses Syndrome System Techniques Testing Tissues Toxic effect X Inactivation age related axonal degeneration conditional mutant exosome experimental study in vivo in vivo Model induced pluripotent stem cell innovation insight late endosome loss of function mutation male mutant mutation carrier nervous system disorder new therapeutic target novel therapeutics patient oriented research patient registry progressive neurodegeneration proteostasis tau Proteins tau mutation tissue mosaicism tool translational approach translational neuroscience ultra high resolution

项目摘要

PROJECT SUMMARY Human genetics offers a powerful approach to dissect cellular mechanisms in neurodegenerative disease. We are studying new genetic conditions with neurodegeneration caused by mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6, also known as SLC9A6). Dysfunction of the endolysosomal system is a common feature in many neurodegenerative disorders. Loss-of-function mutations in NHE6 in males cause Christianson syndrome (CS), which displays mixed neurodevelopmental and neurodegenerative pathology. My research group has recently discovered adult-onset, neurodegenerative disease in female NHE6 mutation carriers. Data in NHE6-related disease support pathology, including axonal degeneration, cerebellar degeneration, and diffuse tau-related disease. The objective of the research in this R01 proposal is to define the cellular mechanisms that cause NHE6-related neurodegeneration, as well as to develop mechanistic linkages to other related neurodegenerative disorders, including Alzheimer’s disease (AD) and AD-related dementias (ADRD). Our central hypothesis is that loss of NHE6 leads to abnormal maturation of late endosomes, thereby causing aberrant retrograde axonal transport and lysosomal dysfunction. My research group, with our collaborators, is in an excellent position to study NHE6-related neurologic disease, both in males and females, as we have developed unique resources including: an international patient registry with patient phenotypic information; the mouse Nhe6 conditional mutant; a panel of patient-derived iPSC cells with robust controls; and an Nhe6-null rat model. We capitalize on the relative strengths of each experimental model to address our scientific questions. We will pursue the following Specific Aims: 1) Demonstrate that neuronal, cell-autonomous loss of NHE6 function in the mature brain causes neurodegeneration; 2) Determine the mechanism by which loss of NHE6 leads to aberrant endosome maturation, lysosomal function, and retrograde axonal transport; and 3) Determine the extent to which impairments in neuronal connectivity in NHE6-null neurons are mediated by tau- related mechanisms. In these Aims, we study mechanisms in CS, as well as neurodegenerative mechanisms in the female-specific NHE6-related syndrome. This research will have a sustained impact on both fundamental neuronal cell biology and on translational neuroscience. These studies will define the neurodegenerative mechanisms in new genetic diseases in males and females, and will establish linkages with more common neurodegenerative disorders, potentially identifying new therapeutic targets. Additionally, our research uses a powerful integrated translational approach, bridging patient-oriented studies to experimental models. Finally, we are establishing valuable experimental resources for these studies, which we will share broadly in order to maximize their utility for the research community.

项目概要人类遗传学提供了一种强有力的方法来剖析神经退行性疾病的细胞机制。正在研究由 X 连锁内体突变引起的神经变性的新遗传病症 Na+/H+ 交换器 6（NHE6，也称为 SLC9A6）是一种常见的内溶酶体系统功能障碍。男性 NHE6 的功能丧失突变是导致 Christianson 的原因。综合征（CS），显示混合的神经发育和神经退行性病理学。研究小组最近在女性 NHE6 突变携带者中发现了成人发病的神经退行性疾病。 NHE6 相关疾病支持病理学，包括轴突变性、小脑变性和 R01 提案中的研究目标是定义细胞性 tau 相关疾病。导致 NHE6 相关神经变性的机制，以及与其他疾病建立机制联系相关的神经退行性疾病，包括阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD)。我们的中心假设是 NHE6 的缺失会导致晚期内体的异常成熟，从而导致我的研究小组和我们的合作者正在研究异常的逆行轴突运输和溶酶体功能障碍。处于研究男性和女性 NHE6 相关神经系统疾病的绝佳位置，正如我们所研究的那样开发了独特的资源，包括：包含患者表型信息的国际患者登记册；小鼠 Nhe6 条件突变体；一组具有稳健对照和 Nhe6 缺失的患者来源的 iPSC 细胞；我们利用每个实验模型的相对优势来解决我们的科学问题。我们将追求以下具体目标：1）证明神经、细胞自主性丧失。成熟大脑中的 NHE6 功能导致神经退行性变；2) 确定 NHE6 功能丧失的机制； NHE6 导致异常的内体成熟、溶酶体功能和逆行轴突运输；3) 确定 NHE6 缺失神经元中神经元连接损伤由 tau 介导的程度在这些目标中，我们研究 CS 的机制以及神经退行性机制。这项研究将对女性特有的 NHE6 相关综合征产生持续影响。这些研究将定义基础神经细胞生物学和转化神经科学。男性和女性新遗传疾病的神经退行性机制，并将与更常见的神经退行性疾病，有可能确定新的治疗靶点。研究采用强大的综合转化方法，将以患者为导向的研究与实验联系起来最后，我们正在为这些研究建立宝贵的实验资源，我们将分享这些资源。广泛地为了最大限度地发挥其对研究界的效用。