Selvaraj Chandrabose, Vijayalakshmi Periyasamy, Desai Dipali, Manoharan Jayakumar
CsrDD Lab, Bioinformatics Division, Department of Marine Biotechnology, AMET University, East Coast Road, Kanathur, Chennai, India.
Department of Biotechnology and Bioinformatics, Holy Cross College, Tiruchirappalli, Tamil Nadu, India.
Adv Protein Chem Struct Biol. 2025;146:1-34. doi: 10.1016/bs.apcsb.2024.11.008. Epub 2025 Apr 18.
Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are defined by the accumulation of misfolded and aggregated proteins, which impair cellular function and result in progressive neuronal death. This chapter examines the critical function of proteostasis-cellular protein homeostasis-in sustaining neuronal health and its disruption as a key factor in disease progression. Proteostasis is upheld by a complex array of mechanisms, which encompass molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, and mitochondrial quality control. Impairment of these systems leads to protein misfolding and aggregation, resulting in toxic cellular environments that promote neurodegeneration. Novel therapeutic approaches focus on restoring proteostasis through the enhancement of cellular protein folding, degradation, and clearance mechanisms. This encompasses small molecule chaperones, gene therapy, RNA-based treatments, immunotherapy, autophagy inducers, and stem cell-based approaches, each addressing distinct components of the proteostasis network to mitigate or prevent disease progression. While these therapies show potential, challenges persist, such as possible side effects, selective targeting, and the efficacy of blood-brain barrier penetration. Personalized medicine and combination therapies customized to specific disease profiles are increasingly recognized for their potential to improve efficacy and safety. This chapter consolidates recent developments in therapies aimed at proteostasis, addresses the challenges encountered in clinical applications, and outlines potential future directions for transformative treatments. Ongoing research indicates that proteostasis modulation may significantly alter the course of neurodegenerative disease treatment, potentially enhancing patient outcomes and quality of life.
阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩侧索硬化症等神经退行性疾病的特征是错误折叠和聚集的蛋白质积累，这些蛋白质会损害细胞功能并导致神经元进行性死亡。本章探讨蛋白质稳态（细胞内蛋白质平衡）在维持神经元健康方面的关键作用，以及其破坏作为疾病进展的关键因素。蛋白质稳态由一系列复杂的机制维持，这些机制包括分子伴侣、泛素 - 蛋白酶体系统、自噬 - 溶酶体途径和线粒体质量控制。这些系统受损会导致蛋白质错误折叠和聚集，从而产生促进神经退行性变的毒性细胞环境。新型治疗方法专注于通过增强细胞蛋白质折叠、降解和清除机制来恢复蛋白质稳态。这包括小分子伴侣、基因治疗、基于RNA的治疗、免疫治疗、自噬诱导剂和基于干细胞的方法，每种方法都针对蛋白质稳态网络的不同组成部分来减轻或预防疾病进展。虽然这些疗法显示出潜力，但挑战依然存在，如可能的副作用、选择性靶向以及血脑屏障穿透的疗效。针对特定疾病特征定制的个性化医疗和联合疗法因其改善疗效和安全性的潜力而越来越受到认可。本章总结了旨在调节蛋白质稳态的治疗方法的最新进展，探讨了临床应用中遇到的挑战，并概述了变革性治疗的潜在未来方向。正在进行的研究表明，调节蛋白质稳态可能会显著改变神经退行性疾病治疗的进程，有可能提高患者的治疗效果和生活质量。
