Neurodegenerative Mechanisms in Christianson Syndrome and NHE6-Related Disorders

项目总结 人类遗传学为剖析神经退行性疾病的细胞机制提供了一种强有力的方法。我们 正在研究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)。内溶酶系统功能障碍是一种常见的 是许多神经退行性疾病的特征。男性NHE6功能丧失突变导致克里斯汀病 综合征(CS)，表现为神经发育和神经退行性混合病理。我的研究 该小组最近在女性NHE6突变携带者中发现了成人起病、神经退行性疾病。数据 在NHE6相关疾病支持病理学中，包括轴突变性、小脑变性和 弥漫性tau相关疾病。本R01提案中研究的目标是定义细胞 导致NHE6相关神经变性的机制，以及与其他 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的丢失会导致晚期内小体的异常成熟，从而导致 异常逆行轴突运输和溶酶体功能障碍。我的研究小组和我们的合作者是 处于研究NHE6相关神经疾病的极佳位置，无论是男性还是女性，就像我们所做的那样 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； 小鼠NHE6条件突变；一组患者来源的具有强大控制的IPSC细胞；以及NHE6-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。我们将追求以下具体目标：1)证明神经元、细胞自主的丧失 NHE6在成熟大脑中的功能导致神经退化；2)决定了 NHE6导致内体异常成熟、溶酶体功能和逆行轴突运输； 确定NHE6缺失神经元的神经元连接性损伤在多大程度上是由tau- 相关机制。在这些目标中，我们研究了CS的机制以及神经退行性机制 在女性特有的NHE6相关综合征中。这项研究将对这两个国家产生持续的影响 基础神经细胞生物学和翻译神经科学。这些研究将定义 男性和女性新遗传性疾病的神经退行性机制，并将与 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翻译方法，将以患者为中心的研究与实验联系起来 模特们。最后，我们正在为这些研究建立有价值的实验资源，我们将分享这些资源 以最大限度地提高其对研究界的效用。

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.