Activity-dependent release of human alpha-synuclein

近年来，一个有趣的概念，朊病毒样传播的致病蛋白已经出现，这有可能改变神经变性研究。大量的神经元蛋白α-突触核蛋白（α-Syn）是一种致病性蛋白质，可导致蛋白质聚集体（Lewy bodies，LB）的异常聚集，导致帕金森病（Parkinson's disease，PD）、路易体痴呆（dementia with Lewy bodies）和多系统萎缩（multiple systems atrophy）等神经退行性疾病。α-Syn的这种朊病毒样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，在我们对α-Syn扩散的理解中，关于调节α-Syn扩散的遗传和分子因素，其分子身份和释放/摄取机制存在关键差距。对α-Syn传播的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，以加快对机制的理解。在这项提议中，我们对α-Syn的活性依赖性释放特别感兴趣，因为已知的PD风险因素，如创伤性脑损伤（TBI）和睡眠剥夺会增加神经元活性和细胞外α-Syn水平。这项研究的目的是探索α-Syn如何在神经系统的细胞之间传播。具体而言，我们有兴趣研究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是研究神经元活动释放α-Syn的分子和生化特征。在目标2中，我们将检查五个α-Syn突变（A30 P，E46 K，H50 Q，G51 D和A53 T）是否不同地影响活性依赖性释放。在目标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。为此，将检查三组PD引起因素：第1组。PD基因（例如，LRRK 2），导致蛋白质降解缺陷和蛋白质稳态丧失。2组PD基因（例如，parkin）参与PD中的线粒体功能障碍和氧化应激。第三组。环境PD因素（例如，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).