Tezuka Toshiki, Taniguchi Daisuke, Sano Mariko, Shimada Tomoyo, Oji Yutaka, Tsunemi Taiji, Ikeda Aya, Li Yuanzhe, Yoshino Hiroyo, Ogata Jun, Shiba-Fukushima Kahori, Funayama Manabu, Nishioka Kenya, Imai Yuzuru, Hattori Nobutaka
Department of Neurology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan.
Department of Neurology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
NPJ Parkinsons Dis. 2022 Aug 5;8(1):97. doi: 10.1038/s41531-022-00367-y.
Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson's disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian populations. The patient exhibited levodopa-responsive parkinsonism at the early stage and visual hallucinations at the advanced stage. The pathological study revealed diffuse Lewy bodies with neurofibrillary tangles, amyloid plaques, and mild signs of neuroinflammation. Biochemically, detergent-insoluble phospho-α-synuclein was accumulated in the frontal, temporal, entorhinal cortexes, and putamen, consistent with the pathological observations. Elevated phosphorylation of Rab10, a substrate of LRRK2, was also prominent in various brain regions. In conclusion, G2385R appears to increase LRRK2 kinase activity in the human brain, inducing a deleterious brain environment that causes Lewy body pathology.
富含亮氨酸重复激酶2（LRRK2）中的错义变异会导致家族性和散发性帕金森病（PD）。携带LRRK2变异的PD患者的病理特征有所不同。在此，我们报告一例尸检病例，该病例携带LRRK2 G2385R变异，这是一种主要出现在亚洲人群中的PD风险变异。患者在疾病早期表现为左旋多巴反应性帕金森综合征，晚期出现视幻觉。病理研究显示存在弥漫性路易小体，并伴有神经原纤维缠结、淀粉样斑块以及轻度神经炎症迹象。生化分析表明，去污剂不溶性磷酸化α-突触核蛋白在额叶、颞叶、内嗅皮质和壳核中积累，这与病理观察结果一致。LRRK2的底物Rab10的磷酸化水平升高在各个脑区也很显著。总之，G2385R变异似乎会增加人脑中LRRK2激酶的活性，诱导产生导致路易小体病理改变的有害脑环境。
