Institute of Protein Biochemistry, Ulm University, Ulm, Germany.
Department of Physics, Chemistry and Biology, Division of Chemistry, Linköping University, Linköping, Sweden.
J Intern Med. 2018 Mar;283(3):218-237. doi: 10.1111/joim.12732. Epub 2018 Feb 19.
The accumulation of misfolded proteins (MPs), both unique and common, for different diseases is central for many chronic degenerative diseases. In certain patients, MP accumulation is systemic (e.g. TTR amyloid), and in others, this is localized to a specific cell type (e.g. Alzheimer's disease). In neurodegenerative diseases, NDs, it is noticeable that the accumulation of MP progressively spreads throughout the nervous system. Our main hypothesis of this article is that MPs are not only markers but also active carriers of pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding MP conformational variations (polymorphism) and their bearing on spreading of MPs, MP toxicity, as well as MP targeting in imaging and therapy. Neurodegenerative disease (ND) represents a major and growing societal challenge, with millions of people worldwide suffering from Alzheimer's or Parkinson's diseases alone. For all NDs, current treatment is palliative without addressing the primary cause and is not curative. Over recent years, particularly the shape-shifting properties of misfolded proteins and their spreading pathways have been intensively researched. The difficulty in addressing ND has prompted most major pharma companies to severely downsize their nervous system disorder research. Increased academic research is pivotal for filling this void and to translate basic research into tools for medical professionals. Recent discoveries of targeting drug design against MPs and improved model systems to study structure, pathology spreading and toxicity strongly encourage future studies along these lines to provide an opportunity for selective imaging, prognostic diagnosis and therapy.
错误折叠蛋白（MPs）的积累，无论是针对不同疾病的特有还是共有，都是许多慢性退行性疾病的核心。在某些患者中，MP 的积累是全身性的（例如 TTR 淀粉样变性），而在另一些患者中，这种积累局限于特定的细胞类型（例如阿尔茨海默病）。在神经退行性疾病（ND）中，值得注意的是，MP 的积累会逐渐在整个神经系统中扩散。本文的主要假设是，MP 不仅是标志物，而且还是致病性的活性载体。在这里，我们讨论了从综合分子方法角度出发的研究，旨在了解 MP 构象变化（多态性）及其对 MP 扩散、MP 毒性以及在成像和治疗中靶向 MP 的影响。神经退行性疾病（ND）是一个重大且日益严峻的社会挑战，全世界有数百万人仅患有阿尔茨海默病或帕金森病。对于所有的 ND 来说，目前的治疗方法是姑息性的，不能针对根本原因，也无法治愈。近年来，错误折叠蛋白的形状变化特性及其扩散途径受到了广泛的研究。解决 ND 的困难促使大多数大型制药公司大幅缩减其神经系统疾病研究。增加学术研究对于填补这一空白以及将基础研究转化为医疗专业人员的工具至关重要。最近发现了针对 MPs 的靶向药物设计和改进的模型系统，用于研究结构、病理学扩散和毒性，这强烈鼓励沿着这些方向进行未来的研究，为选择性成像、预后诊断和治疗提供机会。
