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：
10164658
负责人：
Eric M Morrow
金额：
$ 7.93万
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/10164658
关键词：
Address Adult Aging Ally 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 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 Resolution Resources Role Site Sorting - Cell Movement 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

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.

项目摘要人类遗传学提供了一种强大的方法，可以剖析神经退行性疾病中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条件 Na+/H+交换6（NHE6，也称为SLC9A6）。许多神经退行性疾病的特征。综合征（CS），显示混合的神经发育和神经退行性小组最近发现了成年人的神经退行性疾病。在NHE6相关疾病的疾病中，包含轴突变性，小脑变性和 R01提案中弥漫性TAU相关的疾病是定义细胞的。引起NHE6相关神经变性的机制相关的神经退行性疾病，包括阿尔茨海默氏病（AD）和与AD相关的痴呆症（ADRD）。我们的中心假设是NHE6的丧失导致异常成熟，从而导致我的研究小组，与我们的合作者相比，轴突运输和溶酶体功能障碍是异常的在男性和女性中，都可以研究NHE6结情的神经系统疾病的绝佳位置，因为我们已经拥有开发了独特的资源，包括：国际患者注册表，具有患者的专注信息）小鼠NHE6条件突变体；大鼠模型。我们利用每个实验模型的相对优势问题。我们将追求以下特定AM：1）成熟大脑中的NHE6功能会导致神经变性； 2） NHE6导致异常的内体成熟，溶酶体功能和轴突运输；确定NHE6-NULL神经元中神经元连通性损伤的程度是由Tauu-介导的相关的机制，我们在CS中研究机制在女性特定的NHE6相关综合征中。基本的神经元细胞生物学和翻译神经科学。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障碍，可能识别出新的治疗剂。研究使用强大的集成翻译方法，以患者为导向的桥梁进行实验最终，我们正在建立宝贵的研究资源为了最大程度地提高研究界的实用性。