Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Department of Geriatric Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
Int J Mol Sci. 2021 Apr 2;22(7):3708. doi: 10.3390/ijms22073708.
() is a major causative gene of late-onset familial Parkinson's disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of associated with PD exhibit increased kinase activity. We herein report a novel variant-p.G2294R-located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient's peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.
LRRK2 是晚发性家族性帕金森病（PD）的主要致病基因。抑制激酶活性被认为具有神经保护作用，因为与 PD 相关的大多数致病性 LRRK2 变异体表现出增强的激酶活性。我们在此报告了一种新型 LRRK2 变异体-p.G2294R，位于 WD40 结构域，通过对家族性 PD 患者的靶向基因面板筛选检测到。先证者表现为晚发性帕金森病伴自主神经功能障碍，对左旋多巴反应良好，无认知下降或精神病。细胞培养实验表明，p.G2294R 在蛋白质水平上高度不稳定。LRRK2 p.G2294R 蛋白在患者外周血淋巴细胞中的表达上调。然而，来自同一外周血的分化巨噬细胞中 LRRK2 蛋白水平降低。此外，我们的实验表明致病性酵母和 α-突触核蛋白纤维的吞噬活性降低。该 PD 病例提供了一个例证，即 LRRK2 活性降低并未以神经保护方式发挥作用。需要进一步研究以阐明中枢神经系统中 LRRK2 表达与改变的 LRRK2 活性引起的发病机制之间的关系。
