Utami Kagistia Hana, Morimoto Satoru, Mitsukura Yasue, Okano Hideyuki
Keio University Regenerative Medicine Research Center, Kanagawa 210-0821, Japan; Faculty of Science and Technology, Keio University, Kanagawa 223-0061, Japan; Division of Neurodegenerative Disease Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo 173-0015, Japan; Keio University iPS Cell Research Center for Intractable Neurological Diseases (KiND), Keio University Global Research Institute, Tokyo 108-0073, Japan.
Keio University Regenerative Medicine Research Center, Kanagawa 210-0821, Japan; Division of Neurodegenerative Disease Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo 173-0015, Japan; Keio University iPS Cell Research Center for Intractable Neurological Diseases (KiND), Keio University Global Research Institute, Tokyo 108-0073, Japan.
Biochim Biophys Acta Gen Subj. 2025 Apr;1869(4):130772. doi: 10.1016/j.bbagen.2025.130772. Epub 2025 Feb 13.
Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease share a common pathological hallmark: the accumulation of misfolded proteins, particularly involving intrinsically disordered proteins (IDPs) like TDP-43, FUS, Tau, α-synuclein, and Huntingtin. These proteins undergo pathological aggregation, forming toxic inclusions that disrupt cellular function. The dysregulation of proteostasis mechanisms, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome system (UIPS), autophagy, and molecular chaperones, exacerbates these proteinopathies by failing to clear misfolded proteins effectively. Emerging therapeutic strategies aim to restore proteostasis through proteasome activators, autophagy enhancers, and chaperone-based interventions to prevent the toxic accumulation of IDPs. Additionally, understanding liquid-liquid phase separation (LLPS) and its role in stress granule dynamics offers novel insights into how aberrant phase transitions contribute to neurodegeneration. By targeting the molecular pathways involved in IDP aggregation and proteostasis regulation, and better understanding the specificity of each component, research in this area will pave the way for innovative therapeutic approaches to combat these neurodegenerative diseases. This review discusses the molecular mechanisms underpinning IDP pathology, highlights recent advancements in drug discovery, and explores the potential of targeting proteostasis machinery to develop effective therapies.
诸如肌萎缩侧索硬化症、阿尔茨海默病、帕金森病和亨廷顿病等神经退行性疾病具有一个共同的病理特征：错误折叠蛋白的积累，特别是涉及如TDP-43、FUS、Tau、α-突触核蛋白和亨廷顿蛋白等内在无序蛋白（IDP）。这些蛋白质发生病理性聚集，形成破坏细胞功能的有毒聚集体。蛋白质稳态机制的失调，包括泛素-蛋白酶体系统（UPS）、非泛素依赖性蛋白酶体系统（UIPS）、自噬和分子伴侣，由于未能有效清除错误折叠的蛋白质而加剧了这些蛋白质病。新兴的治疗策略旨在通过蛋白酶体激活剂、自噬增强剂和基于分子伴侣的干预措施来恢复蛋白质稳态，以防止IDP的毒性积累。此外，了解液-液相分离（LLPS）及其在应激颗粒动态变化中的作用，为异常相变如何导致神经退行性变提供了新的见解。通过靶向参与IDP聚集和蛋白质稳态调节的分子途径，并更好地理解每个成分的特异性，该领域的研究将为对抗这些神经退行性疾病的创新治疗方法铺平道路。这篇综述讨论了IDP病理学的分子机制，强调了药物发现的最新进展，并探讨了靶向蛋白质稳态机制以开发有效疗法的潜力。
