Neurodegenerative Mechanisms in Christianson Syndrome and NHE6-Related Disorders

项目摘要 人类遗传学提供了一个强大的方法来剖析神经退行性疾病的细胞机制。我们 正在研究由X连锁核内体突变引起的神经变性的新遗传条件， Na+/H+交换器6（NHE 6，也称为SLC 9A 6）。内溶酶体系统功能障碍是一种常见的 许多神经退行性疾病的特征。男性NHE 6的功能缺失突变导致Christianson 综合征（CS），其显示混合的神经发育和神经变性病理。我的研究 该小组最近在女性NHE 6突变携带者中发现了成人发病的神经退行性疾病。数据 在NHE 6相关疾病支持病理学中，包括轴突变性、小脑变性， 弥漫性tau蛋白相关疾病本R 01提案中的研究目标是定义蜂窝 导致NHE 6相关神经退行性变的机制，以及与其他神经退行性变的机制联系。 相关的神经退行性疾病，包括阿尔茨海默病（AD）和AD相关的痴呆（ADRD）。 我们的中心假设是NHE 6的缺失导致晚期内体的异常成熟，从而引起 异常逆行轴突运输和溶酶体功能障碍。我的研究小组和我们的合作者， 正如我们所做的那样，我们在研究男性和女性NHE 6相关神经系统疾病方面处于有利地位 开发了独特的资源，包括：具有患者表型信息的国际患者登记处; 小鼠Nhe 6条件突变体;一组具有稳健对照的患者来源的iPSC细胞;和Nhe 6-空 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。 问题.我们将追求以下具体目标：1）证明神经元，细胞自主的损失， 成熟大脑中的NHE 6功能导致神经变性; 2）确定NHE 6功能丧失的机制。 NHE 6导致异常的内体成熟、溶酶体功能和逆行轴突运输;以及3） 确定NHE 6-null神经元中神经元连接的损伤由tau蛋白介导的程度。 相关机制。在这些目标中，我们研究CS的机制，以及神经退行性机制 女性特有的NHE 6相关综合征。这项研究将对双方产生持续的影响 基础神经细胞生物学和转化神经科学。这些研究将确定 神经退行性机制在男性和女性的新的遗传疾病，并将建立联系， 更常见的神经退行性疾病，潜在地确定新的治疗靶点。此外，我们的 研究使用强大的综合转化方法，将以患者为导向的研究与实验性研究相结合。 模型最后，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 为了最大限度地发挥其对研究界的效用。

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.