Christianson Syndrome: a novel endosomal disorder with neurodegeneration

项目总结/摘要 内-溶酶体系统缺陷是神经退行性疾病的常见机制。解释键 内体蛋白的功能将为神经退行性病变提供重要的见解， 阿尔茨海默病（AD）和AD相关性痴呆（AD/ADRD）。这项研究的目的是定义细胞 内体Na+/H+交换器6（NHE 6）蛋白在衰老过程中的作用机制， 在我们的新型NHE 6缺失大鼠模型中的神经退行性疾病。NHE 6中的功能丧失突变导致 男性Christianson综合征（CS），涉及神经发育和神经退行性病变。NHE6 正在AD/ADRD病理学中积极研究突变，包括可能与病理性tau蛋白相关的突变 老化沉积。然而，该领域的一个障碍是小鼠模型不能概括关键， 神经变性病理学，包括tau病理学。为了克服这一点，我们产生了一种新的NHE 6-null大鼠， 模型大鼠在遗传和生理上比小鼠更接近人类。重要的是，大鼠模型改善了 在目前的小鼠模型上表现出tau加工的内源性缺陷。我们的具体目标是：1） 在新的老化CS大鼠模型中证明神经变性和tau病理学; 2）确定 NHE 6功能丧失破坏晚期内体成熟的机制，导致异常的逆行 轴突运输我们采取多学科的方法，如生化方法和超分辨率 成像技术。拟议的工作将使人们更好地了解可能成为 AD/ADRD的治疗靶点。

PROJECT SUMMARY/ABSTRACT Defects in endo-lysosomal system are common mechanisms in neurodegenerative diseases. Elucidating key functions of endosomal proteins will provide crucial insight into the neurodegenerative pathologies such as Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD). The goal of this research is to define cellular mechanism mediated by the endosomal Na+/H+ exchanger 6 (NHE6) protein in aging process and neurodegenerative diseases in our novel NHE6-null rat model. Loss-of-function mutations in NHE6 cause Christianson syndrome (CS) in males, involving neurodevelopmental and neurodegenerative pathologies. NHE6 mutations are being actively studied in AD/ADRD pathologies, including as they may relate to pathological tau deposition in aging. However, a hindrance in this field is that mouse models do not recapitulate key neurodegenerative pathologies, including tau pathology. To overcome this, we generated a new NHE6-null rat model. Rats are genetically and physiologically closer to human than mice. Importantly, the rat model improves on current mouse models by manifesting endogenous defects of tau processing. Our specific aims are: 1) Demonstrate neurodegeneration and tau pathology in the novel aging CS rat model; 2) Determine the mechanisms whereby loss of NHE6 function disrupts late endosome maturation, resulting in aberrant retrograde axonal transport. We take multidisciplinary approaches such as biochemical methods and super-resolution imaging techniques. The proposed work will provide better understanding of mechanisms that may become a therapeutic target for AD/ADRD.