Ivantsik Ouliana, Exarchos Themis P, Vrahatis Aristidis G, Vlamos Panagiotis, Krokidis Marios G
Bioinformatics and Human Electrophysiology Laboratory, Department of Informatics, Ionian University, 49100 Corfu, Greece.
Institute of Digital Biomedicine, University Center for Research and Innovation, Ionian University, 49100 Corfu, Greece.
Biomedicines. 2025 May 9;13(5):1146. doi: 10.3390/biomedicines13051146.
Protein functionality depends on its proper folding, making protein misfolding crucial for the function of proteins and, by extension, cells and the whole organism. Increasing evidence supports the role of protein misfolding in the pathogenesis of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive disease diagnosed at a prevalence of 5 cases per 100,000, with approximately 2-3 patients per 100,000 diagnosed each year. To date, there is no cure, and the disease usually leads to death within 2 to 5 years from diagnosis. There are two types of the disorder: familial ALS (fALS), accounting for approximately 10% of cases, and sporadic (sALS), accounting for the remaining 90%. The hallmark of ALS, regardless of type, is the protein aggregates found in patients' tissues. This suggests that the disruption of proteostasis plays a critical role in the development of the disease. Herein, we stress the distinct factors that lead to protein misfolding and aggregate formation in ALS. Specifically, we highlight several triggering factors affecting protein misfolding, namely mutations, errors in the processes of protein production and trafficking, and failures of folding and chaperone machinery. Gaining a deeper understanding of protein aggregation will improve our comprehension of disease pathogenesis and potentially uncover new therapeutic approaches.
蛋白质的功能取决于其正确折叠，因此蛋白质错误折叠对蛋白质功能至关重要，进而对细胞乃至整个生物体的功能都至关重要。越来越多的证据支持蛋白质错误折叠在神经退行性疾病（如肌萎缩侧索硬化症，ALS）发病机制中的作用。ALS是一种快速进展的疾病，诊断患病率为每10万人中有5例，每年每10万人中约有2至3名患者被诊断出来。迄今为止，尚无治愈方法，该疾病通常在诊断后2至5年内导致死亡。该疾病有两种类型：家族性ALS（fALS），约占病例的10%，以及散发性（sALS），占其余的90%。无论哪种类型，ALS的标志都是在患者组织中发现的蛋白质聚集体。这表明蛋白质稳态的破坏在疾病发展中起关键作用。在此，我们强调导致ALS中蛋白质错误折叠和聚集体形成的不同因素。具体而言，我们突出了几个影响蛋白质错误折叠的触发因素，即突变、蛋白质产生和运输过程中的错误，以及折叠和分子伴侣机制的故障。更深入地了解蛋白质聚集将提高我们对疾病发病机制的理解，并有可能发现新的治疗方法。
