Investigating How Chromatin Remodeling Affects Endocytosis and Synapse Organization

项目摘要 跨膜蛋白β-淀粉样前体蛋白（APP）是阿尔茨海默病病理生理学的核心 疾病（AD）。β-淀粉样蛋白假说认为APP的异常加工导致β-淀粉样蛋白的形成。 淀粉样蛋白聚集体，其具有神经毒性，导致AD中观察到的认知障碍。尽管 APP在AD中的重要性，对其功能或神经元如何调节其表达知之甚少。我们有 发现Kismet（Kis），一种果蝇中的染色质重塑蛋白，调节APP样蛋白的表达， AD中失调的神经元过程。Kis类似于哺乳动物的染色质解旋酶结合 结构域（CHD）蛋白质CHD 7和CHD 8，两者都与神经发育障碍有关 包括CHARGE综合征和自闭症谱系障碍，以及突触功能。的目标 这项建议是为了更好地了解表观遗传染色质重塑蛋白Kis如何调节APP样 动物的表达。kis基因突变导致神经元中APP样蛋白和细胞粘附水平增加 突触处的分子。后者已知与APP和类APP交互。我们假设Kis 通过抑制APP样的突触水平促进突触功能和组织，从而影响 突触囊泡的再循环为了检验这一假设，我们将首先更好地描述功能相互作用 Kis和APP之间的区别然后，我们将确定Kis和类APP是否合作影响 突触囊泡内吞作用并将细胞粘附分子定位于突触。这些数据将帮助我们更好地 了解染色质重塑蛋白如何使突触功能，并提供机制的见解， AD的病理学

Project Summary The transmembrane protein β-amyloid precursor protein (APP) is central to the pathophysiology of Alzheimer’s disease (AD). The β-amyloid hypothesis posits that aberrant processing of APP leads to the formation of β- amyloid aggregates, which are neurotoxic leading to the cognitive impairments observed in AD. Despite the importance of APP in AD, little is known about its function or how neurons regulate its expression. We have found that Kismet (Kis), a chromatin remodeling protein in Drosophila, regulates expression of APP-like and neuronal processes that are dysregulated in AD. Kis is similar to the mammalian chromatin helicase binding domain (CHD) proteins CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively, and synaptic function. The goal of this proposal is to better understand how the epigenetic chromatin remodeling protein, Kis, regulates APP-like expression in animals. Mutations in kis lead to increased levels of APP-like in neurons and of cell adhesion molecules at the synapse. The latter are known to interact with APP and APP-like. We hypothesize that Kis promotes synaptic function and organization by suppressing synaptic levels of APP-like thereby affecting the recycling of synaptic vesicles. To test this hypothesis, we will first better characterize the functional interaction between Kis and APP-like. Then we will determine whether Kis and APP-like work cooperatively to influence synaptic vesicle endocytosis and localize cell adhesion molecules to the synapse. These data will help us better understand how chromatin remodeling proteins enable synapse function and provide mechanistic insight into the pathology of AD.