Rubilar Juan Carlos, Outeiro Tiago Fleming, Klein Andrés D
Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7780272, Chile.
Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073, Göttingen, Germany.
Brain. 2024 Aug 1;147(8):2610-2620. doi: 10.1093/brain/awae070.
Parkinson's disease is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular aetiology of the disease is still unclear. Several cellular pathways have been linked to Parkinson's disease, including the autophagy-lysosome pathway, α-synuclein aggregation and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal β-glucocerebrosidase (GCase), and Parkinson's disease lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid build-up, disrupting lysosomal function and autophagy, thereby triggering α-synuclein accumulation. Additionally, α-synuclein aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-synuclein accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in Parkinson's disease pathogenesis and discuss promising examples of GCase-based therapeutics, such as gene and enzyme replacement therapies, small molecule chaperones and substrate reduction therapies, among others, as potential therapeutic interventions.
帕金森病是一种神经退行性疾病，主要以典型的运动特征而闻名，这些特征是由于黑质中多巴胺能神经元的丧失而出现的。然而，该疾病的确切分子病因仍不清楚。几种细胞途径与帕金森病有关，包括自噬 - 溶酶体途径、α - 突触核蛋白聚集和线粒体功能。有趣的是，编码溶酶体β - 葡萄糖脑苷脂酶（GCase）的基因GBA1与帕金森病之间的机制联系在于GCase在溶酶体和线粒体中的功能相互作用。GCase突变会改变线粒体 - 溶酶体接触位点。在溶酶体中，GCase活性降低会导致糖鞘脂积累，破坏溶酶体功能和自噬，从而引发α - 突触核蛋白积累。此外，α - 突触核蛋白聚集体会降低GCase活性，形成溶酶体功能障碍和α - 突触核蛋白积累的自我延续循环。GCase也可以被导入线粒体，在那里它促进线粒体复合体I的完整性和功能。因此，损害其正常功能的GCase突变会增加线粒体中的氧化应激，而多巴胺在此细胞器中被氧化。反过来，氧化多巴胺加合物的积累会进一步损害GCase活性，形成GCase功能障碍的第二个循环。GCase功能障碍引发的氧化状态还可诱导线粒体DNA损伤，进而导致多巴胺能细胞死亡。在这篇综述中，我们强调了GCase在帕金森病发病机制中的关键作用，并讨论了基于GCase的治疗方法的有前景的例子，如基因和酶替代疗法、小分子伴侣和底物减少疗法等，作为潜在的治疗干预措施。
