Peelaerts Wouter, Baekelandt Veerle
Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium.
J Neurochem. 2016 Oct;139 Suppl 1:256-274. doi: 10.1111/jnc.13595. Epub 2016 Mar 30.
Several decades ago, a mysterious transmissible agent was found responsible for a group of progressive and lethal encephalopathies affecting the nervous system of both animals and humans. This infectious agent showed a strain-encoded manner of inheritance even though it lacked nucleic acids. The identification of infectious proteins resolved this apparent conundrum. Misfolded infectious protein particles, or prions, were found to exist as conformational isomers with a unique fingerprint that can be faithfully passaged to next generations. Protein-based strain-encoded inheritance is characterized by strain-specific infectivity and symptomatology. It is found in diverse organisms, such as yeast, fungi, and mammals. Now, this concept is revisited to examine the pathological role of amyloid proteins involved in neurodegenerative diseases where it might underlie certain types of dementia and motor-related neurodegenerative disorders. Given the discovery of the SNCA gene and the identification of its gene product, ɑ-synuclein (ɑ-SYN), as the main histopathological component of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, the scientific community was left puzzled by the fact that a single protein appeared to be involved in different diseases with diverging clinical phenotypes. Recent studies are now indicating that ɑ-SYN may act in a way similar to prions and that ɑ-SYN misfolded structural variants may behave as strains with distinct biochemical and functional properties inducing specific phenotypic traits, which might finally provide an explanation for the clinical heterogeneity observed between Parkinson's disease, MSA, and dementia with Lewy bodies patients. These crucial new findings may pave the way for unexplored therapeutic avenues and identification of new potential biomarkers. Parkinson's disease and other synucleinopathies share ɑ-synuclein deposits as a common histopathological hallmark. New and ongoing developments are now showing that variations in the aggregation process and the formation of ɑ-synuclein strains may be paralleled by the development of distinct synucleinopathies. Here, we review the recent developments and the role of strains in synucleinopathies. This article is part of a special issue on Parkinson disease.
几十年前，人们发现一种神秘的可传播因子是导致一组影响动物和人类神经系统的进行性致死性脑病的原因。这种传染性因子即使缺乏核酸，也呈现出一种由毒株编码的遗传方式。传染性蛋白质的发现解决了这一明显的难题。人们发现错误折叠的传染性蛋白质颗粒，即朊病毒，以构象异构体的形式存在，具有独特的指纹图谱，能够忠实地传递给下一代。基于蛋白质的毒株编码遗传的特点是毒株特异性感染性和症状学。它存在于多种生物体中，如酵母、真菌和哺乳动物。现在，这一概念被重新审视，以研究淀粉样蛋白在神经退行性疾病中的病理作用，而淀粉样蛋白可能是某些类型痴呆和运动相关神经退行性疾病的基础。鉴于SNCA基因的发现以及其基因产物α-突触核蛋白（α-SYN）被确定为帕金森病、路易体痴呆和多系统萎缩的主要组织病理学成分，科学界对单一蛋白质似乎参与了具有不同临床表型的不同疾病这一事实感到困惑。最近的研究表明，α-SYN的行为方式可能与朊病毒类似，并且α-SYN错误折叠的结构变体可能表现为具有不同生化和功能特性的毒株，从而诱导特定的表型特征，这最终可能为帕金森病、多系统萎缩和路易体痴呆患者之间观察到的临床异质性提供一种解释。这些至关重要的新发现可能为未探索的治疗途径和新的潜在生物标志物的鉴定铺平道路。帕金森病和其他突触核蛋白病都有α-突触核蛋白沉积这一共同的组织病理学特征。新的和正在进行的研究表明，聚集过程的变化和α-突触核蛋白毒株的形成可能与不同突触核蛋白病的发展平行。在这里，我们回顾了突触核蛋白病的最新进展以及毒株在其中的作用。本文是帕金森病特刊的一部分。
