Antico Odetta, Thompson Paul W, Hertz Nicholas T, Muqit Miratul M K, Parton Laura E
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
Nat Rev Drug Discov. 2025 Apr;24(4):276-299. doi: 10.1038/s41573-024-01105-0. Epub 2025 Jan 14.
Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.
线粒体功能障碍是包括帕金森病、肌萎缩侧索硬化症、阿尔茨海默病和亨廷顿病在内的特发性神经退行性疾病的一个标志。帕金森病和肌萎缩侧索硬化症的家族形式通常以与线粒体自噬缺陷相关的基因突变为特征。因此，增强线粒体自噬途径可能代表了一种针对神经退行性疾病潜在致病原因的新型治疗方法，具有提供神经保护和疾病修饰的潜力，这是一个重要的未满足需求。越来越多基于基因、分子和临床前模型的证据现在支持在神经退行性疾病中靶向线粒体自噬。尽管面临临床开发挑战，但基于小分子的选择性增强线粒体自噬的方法——即USP30抑制剂和PINK1激活剂——首次进入I期临床试验。
