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：
9811045
负责人：
Eric M Morrow
金额：
$ 96.38万
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/9811045
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 Dementia 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。我们正在研究由X连锁内体突变引起的神经变性的新遗传条件 Na+/H+交换器6（NHE6，也称为SLC9A6）。内溶血系统功能障碍是常见的许多神经退行性疾病的特征。男性NHE6的功能丧失突变导致克里斯蒂安森综合征（CS），它显示混合神经发育和神经退行性病理。我的研究小组最近发现了雌性NHE6突变载体中的成年神经退行性疾病。数据在NHE6相关疾病中，包括轴突变性，小脑变性和弥漫性tau相关疾病。该R01提案中该研究的目的是定义细胞引起NHE6相关神经变性的机制，以及发展与其他的机械联系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的损失导致晚期内体的异常成熟，从而导致异常逆行轴突运输和溶酶体功能障碍。我的研究小组与我们的合作者是在男性和女性中都可以研究NHE6相关的神经疾病的绝佳位置，因为我们已经拥有开发了独特的资源，包括：具有患者表型信息的国际患者注册表；这小鼠NHE6条件突变体；具有健壮对照的患者衍生的IPSC细胞面板；和NHE6-NULL 大鼠模型。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。我们将追求以下特定目的：1）证明神经元的细胞自治损失成熟大脑中的NHE6功能会导致神经变性。 2）确定损失的机制 NHE6导致内体成熟，溶酶体功能和逆行轴突转运。 3）确定NHE6-NULL神经元中神经元连通性损伤的程度是由Tau-介导的相关机制。在这些目标中，我们研究CS中的机制以及神经退行性机制在女性特异性NHE6相关综合征中。这项研究将对两者产生持续的影响基本神经元细胞生物学和转化神经科学。这些研究将定义男性和女性的新遗传疾病中的神经退行性机制，并将与更常见的神经退行性疾病，有可能识别新的治疗靶点。另外，我们的研究使用强大的综合翻译方法，将面向患者的研究桥接到实验型号。最后，我们正在为这些研究建立宝贵的实验资源，我们将分享为了最大程度地提高其对研究界的实用性。