Meade Richard M, Williams Robert J, Mason Jody M
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY UK.
NPJ Parkinsons Dis. 2020 Aug 19;6:17. doi: 10.1038/s41531-020-00122-1. eCollection 2020.
α-Synuclein (αS) deposition is a defining characteristic of Parkinson's disease (PD) pathology, and other synucleinopathies. αS aggregates in disease, leading to the generation of neuronal inclusions known as Lewy bodies. These accumulate in the cytoplasmic space of dopaminergic neurons in the region of the brain, causing cell death, resulting in decreased dopamine levels, and ultimately PD symptoms. To date, a significant proportion of structural information has arisen from in vitro studies using recombinantly purified forms of the protein, often failing to acknowledge that αS is natively located in the presence of phospholipids, where it likely plays a direct role in regulating synaptic vesicle function and neurotransmission. Here we present a series of macromolecular αS assemblies not previously described that form in the presence of lipid vesicles. These fibrillar structures are striking in both their large size relative to those previously reported and by their varying helical content, from ribbons to wave-like helices of long pitch shortening to those more compact and bulkier. These studies provide the foundation for more detailed structural analysis, and may offer new possibilities to further define disease-relevant versions of the protein that are accessible to pharmacological intervention.
α-突触核蛋白（αS）沉积是帕金森病（PD）病理学以及其他突触核蛋白病的一个决定性特征。αS在疾病中聚集，导致称为路易小体的神经元内含物的产生。这些在大脑区域的多巴胺能神经元的细胞质空间中积累，导致细胞死亡，导致多巴胺水平降低，并最终引发PD症状。迄今为止，相当一部分结构信息来自使用重组纯化形式的蛋白质进行的体外研究，这些研究常常未能认识到αS天然存在于磷脂环境中，在那里它可能在调节突触小泡功能和神经传递中发挥直接作用。在此，我们展示了一系列以前未描述过的在脂质囊泡存在下形成的大分子αS聚集体。这些纤维状结构不仅相对于先前报道的结构尺寸大，而且其螺旋含量各异，从带状到长间距缩短的波浪状螺旋，再到更紧凑、更庞大的螺旋，令人瞩目。这些研究为更详细的结构分析奠定了基础，并可能为进一步定义可进行药物干预的与疾病相关的蛋白质版本提供新的可能性。
