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)在阿尔茨海默病的病理生理学中起中心作用 疾病(AD)。β-淀粉样蛋白假说认为APP的异常加工导致β的形成。 淀粉样蛋白聚集体，它具有神经毒性，导致AD患者的认知障碍。尽管 APP在AD中的重要性，人们对其功能或神经元如何调节其表达知之甚少。我们有 研究发现，果蝇染色质重塑蛋白Kismet(Kis)调节APP样蛋白和 阿尔茨海默病中神经过程的失调。KIS类似于哺乳动物染色质解旋酶的结合 结构域(CHD)蛋白CHD7和CHD8，两者都与神经发育障碍有关 分别包括充电综合征和自闭症谱系障碍，以及突触功能。的目标是 这项建议是为了更好地了解表观遗传的染色质重塑蛋白Kis如何调节APP样蛋白 在动物身上的表达。KI基因突变导致神经元内APP样蛋白水平增加和细胞黏附 突触上的分子。后者与APP和类APP交互是已知的。我们假设基斯 通过抑制类APP的突触水平促进突触功能和组织，从而影响 突触小泡的循环。为了验证这一假设，我们将首先更好地描述功能交互 在Kis和类似应用程序之间。然后我们将确定KIS和类似APP是否协同工作以影响 突触小泡内吞，并将细胞黏附分子定位于突触。这些数据将帮助我们更好地 了解染色质重塑蛋白如何实现突触功能，并提供对 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.