Mutations in GBA1, which encode for the protein glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease and dementia with Lewy bodies. In addition, growing evidence now suggests that the loss of GCase activity is also involved in onset of all forms of Parkinson's disease, dementia with Lewy bodies, and other dementias, such as progranulin-linked frontal temporal dementia. As a result, there is significant interest in developing GCase-targeted therapies that have the potential to stop or slow progression of these diseases. Despite this interest in GCase as a therapeutic target, there is significant inconsistency in the methodology for measuring GCase enzymatic activity in disease-modeling systems and patient populations, which could hinder progress in developing GCase therapies. In this review, we discuss the different strategies that have been developed to assess GCase activity and highlight the specific strengths and weaknesses of these approaches as well as the gaps that remain. We also discuss the current and potential role of these different methodologies in preclinical and clinical development of GCase-targeted therapies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

中文翻译：

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溶酶体葡糖脑苷脂酶活性测定策略的评价

GBA1中的突变编码葡萄糖脑苷脂酶 (GCase) 的蛋白质是帕金森病和路易体痴呆最常见的遗传风险因素。此外，现在越来越多的证据表明，GCase 活性的丧失也与所有形式的帕金森氏病、路易体痴呆和其他痴呆症（例如颗粒蛋白相关的额颞叶痴呆）的发作有关。因此，人们对开发有可能阻止或减缓这些疾病进展的 GCase 靶向疗法产生了浓厚的兴趣。尽管人们对将 GCase 作为治疗靶点感兴趣，但在疾病建模系统和患者群体中测量 GCase 酶活性的方法存在显着的不一致，这可能会阻碍 GCase 疗法开发的进展。在这篇评论中，我们讨论了为评估 GCase 活性而制定的不同策略，并强调了这些方法的具体优势和劣势以及仍然存在的差距。我们还讨论了这些不同方法在 GCase 靶向治疗的临床前和临床开发中的当前和潜在作用。© 2021 作者。由 Wiley Periodicals LLC 代表国际帕金森和运动障碍协会出版的运动障碍