Neuronal Autophagy: a Cell-Autonomous Protection Mechanism

我们的长期目标是了解自噬的神经保护机制， 自噬的治疗靶点，以治疗与以下相关的神经退行性疾病： 神经元内蛋白质聚集体。自噬在神经元中的生理功能是维持 代谢稳态，并通过不断降解作为质量控制。重要的是 神经元的组成性自噬具有高度的选择性，靶向特定的蛋白质和细胞器 货物的溶酶体降解。然而，选择性的分子机制 自噬在神经元中的特征仍然很差。越来越多的证据表明， 自噬是通过一个称为自噬受体的蛋白质家族介导的， 其特征在于能够识别货物蛋白上的降解信号， LC 3/GABARAP蛋白对自噬体形成的影响。我们目前的目标是了解 神经元自噬的生理功能和选择性，并剖析了自噬的分子机制。 选择性自噬清除疾病相关蛋白的机制，特别是与 阿尔茨海默病（AD）。AD的病理特征是细胞外淀粉样斑块 和神经元内的神经元性tau蛋白缠结。最近AD临床试验的失败表明了 更深入地了解致病途径，开发新的治疗方法， AD的策略。事实上，多种证据表明，基础自噬阻止了细胞的增殖。 磷酸化tau（p-tau）的积累。此外，我们的实验室和其他人认为， 自噬选择性降解淀粉样β前体蛋白（APP）及其代谢物（例如C-APP）。 末端片段或CTF和Aβ）。我们假设自噬选择性地清除有毒物质 tau种类和APP/APP代谢物通过特异性自噬受体。鉴于日益增加的 有证据表明自噬控制了p-Tau，APP及其代谢物的水平，我们 提出，靶向选择性自噬途径提供了一种新的疾病修饰策略， AD的治疗。我们提出以下目的来检验上述假设：目的1。确定 神经元自噬的生理功能和选择性。目标2.检查 选择性自噬在调节tau稳态和tau蛋白病中的作用。目标3： 确定APP及其代谢物清除中选择性自噬的机制。 我们试图建立选择性自噬如何调节细胞内稳态的分子基础。 CNS中两种最重要的AD相关蛋白，磷酸化tau和APP（及其代谢产物）; 我们的研究有望深入了解AD的发病机制并协助研究 开发用于AD治疗的新型疾病改善策略。

Our long-term goal is to understand neuroprotective mechanisms of autophagy and identify therapeutic targets of autophagy to treat neurodegenerative diseases associated with intraneuronal protein aggregates. The physiological function of autophagy in neuron is to maintain metabolic homeostasis and serve as quality control through constant degradation. Importantly, the constitutive autophagy in neurons shows high selectivity, targeting specific protein and organelle cargo to the lysosomal degradation. However, the molecular mechanism for the selective autophagy remains poorly characterized in neurons. Increasing evidence shows that selective autophagy is mediated through a family of proteins called autophagy receptors, which are characterized by the ability to recognize degradation signals on cargo proteins and also bind LC3/GABARAP proteins on the forming autophagosome. Our current goal is to understand the physiological function and selective nature of autophagy in neurons and dissect the molecular mechanism whereby selective autophagy clears disease related proteins particularly related to Alzheimer’s disease (AD). AD is characterized pathologically by the extracellular amyloid plaques and intraneuronal neurofibrillary tau tangles. Recent failures of AD clinical trials show the urgency to have deeper understanding of the pathogenic pathways and develop novel therapeutic strategies of AD. Indeed, multiple lines of evidence suggest that basal autophagy prevents the accumulation of phosphorylated tau (p-tau). Furthermore, our lab and others suggests that autophagy selectively degrades amyloid β precursor protein (APP) and its metabolites (e.g. C- terminal fragments or CTFs and Aβ). We hypothesize that autophagy selectively removes toxic tau species and APP/APP metabolites through specific autophagy receptors. Given increasing evidence implicating autophagy in controlling the levels of p-Tau, APP and its metabolites, we propose that targeting selective autophagy pathway offers a novel disease-modifying strategy for the treatment of AD. We propose the following Aims to test above hypothesis: Aim 1. Determine the physiological function and the selective nature of autophagy in neurons. Aim 2. Examine the role for selective autophagy in the regulation of tau homeostasis and tauopathies. Aim 3. Determine the mechanism for selective autophagy in the clearance of APP and its metabolites. We seek to establish molecular basis for how selective autophagy regulates the homeostasis of the two most important AD related proteins, phospho-tau and APP (and its metabolites) in CNS; our study is expected to provides insight into the pathogenesis of AD and assist in the development of novel disease-modifying strategy for AD treatment.