突触蛋白SCAMP5对自噬和神经毒性蛋白传播的调控作用及机制

Due to increased longevity, neurodegenerative diseases, which include the common Alzheimer and Parkinson diseases, and the less common amyotrophic lateral sclerosis (ALS) and Huntington disease, have become major factors affecting public health. Because of the chronic and irreversible nature of these disorders, neurodegenerative diseases have grown to a huge financial burden to the affected families and societies, and have taken enormous emotional toll on the family members of the patients. Unfortunately, current treatment options are limited to symptom management. There is no cure for these diseases. Thus, there is a pressing need for the research community and pharmaceutical industry to develop novel disease-modifying therapeutics for neurodegenerative diseases. In this proposal, we will study the expression and function of a synaptic protein, SCAMP5, during neurodegeneration using cellular, C. elagans, and drosophila models and a variety of novel techniques. Our preliminary studies have suggested that SCAMP5 as a potentially important regulator for autophagy and the transmission of neurotoxic proteins, and these two mechanisms will be the main focus of our investigation. We hypothesize that SCAMP5 is a novel regulator of autophagy and neurotoxic protein transmission, and is induced during pathological conditions. Therefore，this study will shed light on the regulation of two important disease-causing mechanisms, autohphagy and toxic protein transmission, by a synaptic protein. The results from our study will generate new insights into the disease treatment.

神经退行性疾病，包括常见的阿尔兹海默症及痴呆，帕金森病及较少见的脊髓侧束硬化症和亨廷顿舞蹈症等，已逐渐成为影响人类健康的杀手。由于慢性及不可逆的特征，这些脑变性疾病对病人家庭、社会造成巨大的负担。然而，目前的治疗方法还只停留在有限的症状控制。对多数退行性疾病无药可用。因此，寻找对退行性疾病有效的治疗手段是各国科研及药物研发界的重要导向。此项研究拟运用细胞、线虫和果蝇多种模式和创新技术对突触蛋白SCAMP5在神经退行性疾病进程中的表达和作用进行深入研究。基于我们大量的前期工作，我们将探讨SCAMP5在自噬、神经毒性蛋白传播这两个神经变性疾病新机制中的作用及机理。我们假设是SCAMP5是一个在病理状态下受诱导的对自噬有抑制作用的，同时促进神经毒性蛋白分泌的细胞毒性辅助因子。这是一个在前沿领域对一个潜在的疾病调控蛋白的功能研究。结果将可能会对对神经变性疾病的治疗提供新的思路和靶点。

世界上多个国家，尤其是我国，已逐渐进入老龄化社会。随老龄化而日趋严重的的神经退行性疾病也日益成为影响老年人群生活品质的最大因素之一。神经退行性疾病中一个共享的机制是神经毒性蛋白的清除、分泌和在细胞间的传播的异常，然而对这些事件的协同调控机制尚不明确。我们在这个课题中发现了一个突触蛋白SCAMP5是一个新的可以同时调节自噬和外泌体的分泌的分子。在细胞受到应激刺激时，SCAMP5的转录水平受自噬活化分子TFEB诱导升高，却导致自噬被抑制。SCAMP5对自噬的抑制发生在自噬小体和溶酶体融合的步骤，并和SCAMP5引起的高尔基体碎片化相关。不仅如此，SCAMP5对自噬的阻碍并没有导致神经毒性蛋白如a-突触核蛋白在细胞内的积累， 而是更快地分泌到胞外。这一过程是由于SCAMP5与外泌体结合并促进蛋白分泌造成。 而SCAMP5在应激情况下又会在产生几个小时后就被蛋白酶体所降解。因此，我们的研究发现了一个细胞内调控蛋白的稳态新途径。在细胞呃内蛋白异常积累时，自噬启动分子TFEB可以通过激活SCAMP5来高效地通过外泌体清除神经毒性蛋白，而不是通过耗费更多能量的自噬通路。然而这一蛋白清除机制也为神经毒性蛋白在细胞间的传播埋下了种子。因此，我们的这项研究为神经退行性疾病的分子机制提供了新的思路。同时我们的研究也发现SCAMP5在阿尔兹海默、帕金森症患者外周血中表达升高，提示这个分子有望成为神经退行性疾病的一个风险指标。