Foressi Nahuel N, Rodríguez Leandro Cruz, Celej M Soledad
Departamento de Química Biológica Ranwel Caputto, Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC, CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de La Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
Biophys Rev. 2024 Dec 2;17(2):491-498. doi: 10.1007/s12551-024-01259-6. eCollection 2025 Apr.
Alzheimer's and Parkinson's diseases are the most common neurodegenerative disorders, causing significant disability and mortality worldwide. Though traditionally classified as Tau and α-synuclein-related disorders, respectively, there is growing evidence of clinical overlap between dementia and Parkinsonism, with comorbidity worsening cognitive impairment and prognosis. Emerging research on liquid-liquid phase separation (LLPS) offers promising insights into novel treatments of these proteinopathies by targeting the phase behavior of the disease-associated proteins. Thus, manipulating condensates has become a focus for developing new therapeutic compounds, termed condensate-modifying drugs (c-mods), by which historically considered undruggable proteins can be targeted. This review offers an overview of bioactive molecules that act as modifiers of Tau and α-synuclein condensates through various mechanisms. The goal is to lay the groundwork for discovering new therapeutic approaches to prevent harmful protein aggregation and treat comorbidity in tau and synucleinopathies.
阿尔茨海默病和帕金森病是最常见的神经退行性疾病，在全球范围内导致严重的残疾和死亡。尽管传统上分别归类为与 Tau 蛋白和α-突触核蛋白相关的疾病，但越来越多的证据表明痴呆症和帕金森综合征在临床上存在重叠，合并症会加重认知障碍和预后。关于液-液相分离（LLPS）的新兴研究通过针对疾病相关蛋白的相行为，为这些蛋白质病的新治疗方法提供了有前景的见解。因此，操纵凝聚物已成为开发新型治疗化合物（称为凝聚物修饰药物，c-mods）的重点，通过这种方法可以靶向历史上被认为不可成药的蛋白质。本综述概述了通过各种机制作为 Tau 蛋白和α-突触核蛋白凝聚物修饰剂的生物活性分子。目的是为发现预防有害蛋白质聚集和治疗 Tau 蛋白病和突触核蛋白病合并症的新治疗方法奠定基础。
