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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.

项目总结