Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Lensfield Road, CambridgeCB2 1EW, UK.
Q Rev Biophys. 2020 Jun 4;49:e22. doi: 10.1017/S0033583520000025.
Neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's diseases (PD), are characterised by the formation of aberrant assemblies of misfolded proteins. The discovery of disease-modifying drugs for these disorders is challenging, in part because we still have a limited understanding of their molecular origins. In this review, we discuss how biophysical approaches can help explain the formation of the aberrant conformational states of proteins whose neurotoxic effects underlie these diseases. We discuss in particular models based on the transgenic expression of amyloid-β (Aβ) and tau in AD, and α-synuclein in PD. Because biophysical methods have enabled an accurate quantification and a detailed understanding of the molecular mechanisms underlying protein misfolding and aggregation in vitro, we expect that the further development of these methods to probe directly the corresponding mechanisms in vivo will open effective routes for diagnostic and therapeutic interventions.
神经退行性疾病，包括阿尔茨海默病（AD）和帕金森病（PD），其特征是异常折叠的蛋白质错误聚集。发现这些疾病的治疗方法具有挑战性，部分原因是我们对其分子起源的了解仍然有限。在这篇综述中，我们讨论了生物物理方法如何帮助解释导致这些疾病的神经毒性作用的蛋白质异常构象状态的形成。我们特别讨论了基于淀粉样β（Aβ）和 tau 在 AD 中的转基因表达，以及α-突触核蛋白在 PD 中的模型。由于生物物理方法能够准确地定量和详细地了解蛋白质错误折叠和聚集的分子机制，我们期望这些方法的进一步发展，直接探测体内相应的机制，将为诊断和治疗干预开辟有效的途径。
