Activity-dependent release of human alpha-synuclein

近年来，出现了一个有趣的概念，即病原蛋白的朊病毒样传播，这有可能改变神经变性研究。丰富的神经元蛋白α-突触核蛋白（α-Syn）是一种致病蛋白，可导致称为路易体（LBs）的蛋白聚集体的异常积聚，导致帕金森病（PD）、路易体痴呆、多系统萎缩等多种神经退行性疾病。这种类似朊病毒的α-Syn扩散是人类神经退行性疾病进展中最令人兴奋的新发现之一。尽管如此，我们对α-Syn扩散调控的遗传和分子因素、α-Syn的分子特性和释放/摄取机制的理解仍存在重大空白。对α-Syn传播分子机制的新见解将揭示减缓甚至停止PD进展的潜在治疗靶点。我们需要的是一种新的遗传模型，以加快对机理的理解。在这项研究中，我们对α-Syn的活动依赖性释放特别感兴趣，因为已知的PD危险因素如创伤性脑损伤（TBI）和睡眠剥夺会增加神经元活动和α-Syn的细胞外水平。本研究的目的是探索α-Syn如何在神经系统细胞间传播。具体来说，我们感兴趣的是研究α-Syn突变和遗传/分子因素如何影响其活性依赖性释放。目的1：通过神经元活动表征α-Syn释放的分子和生化特征。在Aim 2中，我们将检测五种α-Syn突变（A30P、E46K、H50Q、G51D和A53T）对活性依赖性释放的影响是否不同。在Aim 3中，我们将研究活性依赖性α-Syn释放是否受到其他PD基因和环境因素的影响。本研究将研究三组帕金森病的病因：第一组。PD基因（如LRRK2）导致蛋白质降解缺陷和蛋白质稳态丧失。组2。PD基因（如parkin）参与PD的线粒体功能障碍和氧化应激。Group3。环境PD因素（如鱼藤酮）。

In recent years, an intriguing concept of prion-like spreading of pathogenic proteins has emerged, which has the potential to transform neurodegeneration research. Abundant neuronal protein alpha-synuclein (α-Syn) is a pathogenic protein leading to the abnormal accumulation of protein aggregates, called Lewy bodies (LBs) that cause several neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. This prion-like spreading of α-Syn is one of the most exciting new discoveries in the progression of human neurodegenerative diseases. Nonetheless, there are critical gaps in our understanding of α-Syn spreading regarding genetic & molecular factors regulating α-Syn spreading, its molecular identity and release/uptake mechanisms. New insights into the molecular mechanisms of α-Syn propagation will uncover potential therapeutic targets for slowing or even halting PD progression. What is needed is a new genetic model to speed improved mechanistic understanding. In this proposal, we are especially interested in activity-dependent release of α-Syn since known PD risk factors such as traumatic brain injury (TBI) and sleep deprivation increases neuronal activity and extracellular levels of α-Syn. The goal of this proposed study is to explore how α-Syn spreads between cells in the nervous system. Specifically, we are interested in studying how α-Syn mutations and genetic/molecular factors affect its activity-dependent release. Aim 1 is to characterize molecular and biochemical profiles of released α-Syn by neuronal activity. In Aim 2, we will examine whether five α-Syn mutations (A30P, E46K, H50Q, G51D & A53T) differently affect activity-dependent release. In Aim 3, we will examine whether activity-dependent α-Syn release is affected by other PD genes and environmental factors. Three groups of PD causing factors will be examined in this aim: Group 1. PD genes (e.g., LRRK2) causing defects in protein degradation and loss of proteostasis. Group 2. PD genes (e.g., parkin) involved in mitochondrial dysfunction and oxidative stress in PD. Group3. Environmental PD factors (e.g., rotenone).