Progenra Inc., 271A Great Valley Parkway, Malvern, PA, 19355, USA.
Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, USA.
Neuromolecular Med. 2023 Sep;25(3):313-329. doi: 10.1007/s12017-023-08738-1. Epub 2023 Feb 5.
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell's response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.
帕金森病（PD）是最常见的神经退行性运动障碍。目前尚无能够减缓或阻止多巴胺能神经元进行性丧失的治疗方法，而多巴胺能神经元的丧失是主要的临床症状。目前批准的 PD 药物可以通过增加大脑多巴胺含量或活性来提供症状缓解；然而，这种缓解是暂时的，随着神经退行性变的不可避免进展，其效果会减弱。由于对 PD 相关神经退行性变的根本原因缺乏充分的了解，疾病修饰性神经保护疗法的发现和开发一直受到阻碍。PD 的病因涉及遗传和环境因素的结合。尽管尚未出现单一病因，但遗传、细胞生物学和神经病理学证据表明与线粒体功能障碍和蛋白质聚集有关。PD 死后大脑显示出特征性的路易体神经元内包涵体，由聚集的α-突触核蛋白组成，表明无法降解错误折叠的蛋白质。编码α-突触核蛋白的基因突变以及 E3 泛素连接酶 Parkin 导致罕见的遗传性 PD 形式。虽然许多泛素连接酶用泛素链标记蛋白质，以标记蛋白质通过蛋白酶体进行降解，但 Parkin 已被证明可以标记功能失调的线粒体进行线粒体自噬降解。泛素蛋白酶体系统参与细胞对线粒体损伤的反应的几个方面，为增强线粒体自噬并可能阻止 PD 进展提供了许多治疗机会。本综述考察了这种 UPS 调节剂的作用和治疗潜力，以泛素化和去泛素化酶为例。
