Lim Kwang Hun
Department of Chemistry, East Carolina University, Greenville, NC, United States.
Front Mol Neurosci. 2019 Jul 9;12:158. doi: 10.3389/fnmol.2019.00158. eCollection 2019.
Numerous neurodegenerative diseases including prion, Alzheimer's and Parkinson's diseases are characterized by accumulation of protein aggregates in brain. Prion disease is unique in that the natively folded prion protein forms diverse misfolded aggregates with distinct molecular conformations (strains), which underlie different disease phenotypes. In addition, the conformational strains are able to self-propagate their unique conformations by recruiting normal protein monomers and converting their conformations to misfolded conformers. There is an increasing body of evidence that suggests other aggregation-prone proteins including tau and α-synuclein associated with Alzheimer's and Parkinson's diseases, respectively, also behave like a prion that has conformational strains with self-propagation (seeding) property. Moreover, misfolded protein aggregates can promote misfolding and aggregation of different proteins through cross-seeding, which might be associated with co-occurrence of multiple neurodegenerative diseases in the same patient. Elucidation of diverse conformational strains with self-propagation capability and of molecular basis for the cross-talk between misfolded proteins is essential to the development of effective therapeutic intervention.
包括朊病毒病、阿尔茨海默病和帕金森病在内的许多神经退行性疾病的特征是大脑中蛋白质聚集体的积累。朊病毒病的独特之处在于，天然折叠的朊病毒蛋白会形成具有不同分子构象（毒株）的多种错误折叠聚集体，这些构象是不同疾病表型的基础。此外，构象毒株能够通过招募正常蛋白质单体并将其构象转化为错误折叠的构象异构体来自我传播其独特构象。越来越多的证据表明，其他易聚集的蛋白质，分别与阿尔茨海默病和帕金森病相关的tau蛋白和α-突触核蛋白，也表现得像具有构象毒株和自我传播（种子）特性的朊病毒。此外，错误折叠的蛋白质聚集体可以通过交叉种子作用促进不同蛋白质的错误折叠和聚集，这可能与同一患者中多种神经退行性疾病的共现有关。阐明具有自我传播能力的多种构象毒株以及错误折叠蛋白质之间相互作用的分子基础对于开发有效的治疗干预措施至关重要。
