Autophagy and Neurodegeneration

 描述（由申请人提供）：在过去的10年中，溶酶体介导的降解途径巨自噬在成人发病神经变性领域获得了突出地位。大自噬是一种重要的细胞途径，负责消除胞质蛋白质，脂质和细胞器。它是三种自噬形式中最保守的一种，它在哺乳动物中的重要性可以在从发育的最早阶段到衰老大脑的维持的广泛过程中看到。虽然神经元是最早进行大自噬研究的细胞类型之一，但随后在肝脏和酵母中的生化和遗传研究导致对神经元大自噬的兴趣减弱。尽管如此，随着巨自噬在神经退行性疾病中的重要性不断增加，很明显，如果我们要真正了解这一重要途径如何影响成人大脑，我们必须重新关注神经巨自噬。在这项提案中，我们将研究两个关键问题，这两个问题将定义基本的宏观自噬事件在健康和患病的成人大脑中是如何相关的。在目标1中，我们将定义膜胆固醇如何影响宏观自噬，以及胆固醇稳态的破坏如何导致哺乳动物大脑中功能失调的自噬。然后在目标2中，我们将确定是否聚集倾向的蛋白质确实被成年大脑中的大自噬消除，并建立这个过程所必需的最小成分。通过回答这些问题，我们不仅将进一步了解关键的宏观自噬过程的机制，而且我们还将进一步了解宏观自噬如何影响神经退行性疾病。

 DESCRIPTION (provided by applicant): Over the last 10 years, the lysosome-mediated degradation pathway macroautophagy has gained prominence in the field of adult onset neurodegeneration. Macroautophagy is an essential cellular pathway responsible for the elimination of cytosolic proteins, lipids and organelles. It is the most conserved of the three forms of autophagy, and its importance in mammals can be seen in a wide array of processes from the earliest stages of development to the maintenance of the aging brain. Although neurons were among the earliest cell types to be examined for macroautophagy, subsequent biochemical and genetic studies in liver and yeast caused the interest in neuronal macroautophagy to wane. Nonetheless, as the importance of macroautophagy in neurodegenerative diseases continues to grow, it is clear that we must refocus our attention on neural macroautophagy if we are truly to understand how this essential pathway impacts the adult brain. In this proposal, we will examine two key questions that will define how fundamental macroautophagic events are relevant in the healthy and diseased adult brain. In Aim 1, we will define how membrane cholesterol impacts macroautophagy, and how disruptions in cholesterol homeostasis may lead to dysfunctional autophagy in the mammalian brain. Then in Aim 2, we will determine if aggregation-prone proteins are indeed eliminated by macroautophagy in the adult brain, and establish the minimal components essential for this process. By answering these questions, we will not only further our mechanistic understanding of key macroautophagic processes, but we will also understand them in a context that will further our understanding of how macroautophagy can impact neurodegenerative disease.