Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Neuron. 2020 Mar 4;105(5):822-836.e7. doi: 10.1016/j.neuron.2019.12.004. Epub 2019 Dec 30.
Mutations in the GBA1 gene are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal lipid hydrolase glucocerebrosidase (GCase), and its activity has been linked to accumulation of α-synuclein. The current study systematically examines the relationship between GCase activity and both pathogenic and non-pathogenic forms of α-synuclein in primary hippocampal, cortical, and midbrain neuron and astrocyte cultures, as well as in transgenic mice and a non-transgenic mouse model of PD. We find that reduced GCase activity does not result in aggregation of α-synuclein. However, in the context of extant misfolded α-synuclein, GCase activity modulates neuronal susceptibility to pathology. Furthermore, this modulation does not depend on neuron type but rather is driven by the level of pathological α-synuclein seeds. This study has implications for understanding how GBA1 mutations influence PD pathogenesis and provides a platform for testing novel therapeutics.
GBA1 基因突变是帕金森病 (PD) 和路易体痴呆 (DLB) 的最常见遗传风险因素。GBA1 编码溶酶体脂质水解酶葡萄糖脑苷脂酶 (GCase)，其活性与α-突触核蛋白的积累有关。本研究系统地研究了 GCase 活性与原发性海马、皮质和中脑神经元和星形胶质细胞培养物以及转基因小鼠和非转基因 PD 小鼠模型中致病性和非致病性 α-突触核蛋白之间的关系。我们发现，GCase 活性降低不会导致 α-突触核蛋白聚集。然而，在现存的错误折叠的 α-突触核蛋白的情况下，GCase 活性调节神经元对病理学的易感性。此外，这种调节不依赖于神经元类型，而是由病理性 α-突触核蛋白种子的水平驱动。这项研究对于理解 GBA1 突变如何影响 PD 的发病机制具有重要意义，并为测试新的治疗方法提供了一个平台。
