PDF(Pubmed)
Abstract：
GBA1-associated Parkinson\'s disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson\'s disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: \'haploinsufficiency,\' where a single functional gene copy fails to produce a sufficient amount of GCase, and \'gain of function,\' where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the \'gain of function\' mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.
摘要：
GBA1相关的帕金森病（GBA1-PD）越来越被认为是帕金森病谱中的一个独特实体。这篇综述探讨了其独特的病理生理学特征，临床进展,以及将GBA1-PD与特发性帕金森病（iPD）区分开来的遗传基础。GBA1-PD通常表现为发病较早和进展较快，对标准PD药物反应不佳。与iPD相比，它的特点是明显的认知障碍和更高的非运动症状负担。此外,GBA1-PD患者通常在脑内表现出更广泛的路易体分布，强调神经退行性过程。GBA1-PD的发病机制与GBA1基因突变密切相关,其编码溶酶体酶β-葡糖脑苷脂酶(GCase)。在这次审查中,我们讨论了GBA1突变导致疾病发展的两种机制：如果单个功能基因拷贝不能产生足够量的GCase,和函数的\'增益，当突变的GCase获得直接影响α-突触核蛋白降解的细胞机制的有害特性时，导致α-突触核蛋白聚集和神经元细胞损伤。持续的研究正在推进我们对这些机制如何促进GBA1-PD的发展和进步的理解，“功能增益”机制似乎是最合理的。这篇综述还探讨了GBA1突变对治疗策略的影响，强调需要早期诊断和有针对性的干预措施。目前,与其他药物相比，小分子伴侣显示出最有希望的临床结果。这种临床合成，病态,和分子方面强调了GBA1-PD是一种独特的临床和病理生物学PD表型的断言，需要特定的管理和研究方法来更好地理解和治疗这种衰弱的状况。
