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Long-term inhibition of mutant LRRK2 hyper-kinase activity reduced mouse brain α-synuclein oligomers without adverse effects
npj Parkinson's Disease ( IF 6.7 ) Pub Date : 2022-09-10 , DOI: 10.1038/s41531-022-00386-9
Philip Wing-Lok Ho 1 , Eunice Eun-Seo Chang 1 , Chi-Ting Leung 1 , Huifang Liu 1 , Yasine Malki 1 , Shirley Yin-Yu Pang 1 , Zoe Yuen-Kiu Choi 1 , Yingmin Liang 2 , Weng Seng Lai 3 , Yuefei Ruan 3 , Kenneth Mei-Yee Leung 3 , Susan Yung 4 , Judith Choi-Wo Mak 2 , Michelle Hiu-Wai Kung 1 , David B Ramsden 5 , Shu-Leong Ho 1
Affiliation  

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration in nigrostriatal and cortical brain regions associated with pathogenic α-synuclein (αSyn) aggregate/oligomer accumulation. LRRK2 hyperactivity is a disease-modifying therapeutic target in PD. However, LRRK2 inhibition may be associated with peripheral effects, albeit with unclear clinical consequences. Here, we significantly reduced αSyn oligomer accumulation in mouse striatum through long-term LRRK2 inhibition using GNE-7915 (specific brain-penetrant LRRK2 inhibitor) without causing adverse peripheral effects. GNE-7915 concentrations in wild-type (WT) mouse sera and brain samples reached a peak at 1 h, which gradually decreased over 24 h following a single subcutaneous (100 mg/kg) injection. The same dose in young WT and LRRK2R1441G mutant mice significantly inhibited LRRK2 kinase activity (Thr73-Rab10 and Ser106-Rab12 phosphorylation) in the lung, which dissipated by 72 h post-injection. 14-month-old mutant mice injected with GNE-7915 twice weekly for 18 weeks (equivalent to ~13 human years) exhibited reduced striatal αSyn oligomer and cortical pSer129-αSyn levels, correlating with inhibition of LRRK2 hyperactivity in brain and lung to WT levels. No GNE-7915-treated mice showed increased mortality or morbidity. Unlike reports of abnormalities in lung and kidney at acute high doses of LRRK2 inhibitors, our GNE-7915-treated mice did not exhibit swollen lamellar bodies in type II pneumocytes or abnormal vacuolation in the kidney. Functional and histopathological assessments of lung, kidney and liver, including whole-body plethysmography, urinary albumin-creatinine ratio (ACR), serum alanine aminotransferase (ALT) and serum interleukin-6 (inflammatory marker) did not reveal abnormalities after long-term GNE-7915 treatment. Long-term inhibition of mutant LRRK2 hyper-kinase activity to physiological levels presents an efficacious and safe disease-modifying therapy to ameliorate synucleinopathy in PD.



中文翻译:

长期抑制突变型 LRRK2 超激酶活性可降低小鼠脑 α-突触核蛋白寡聚体而无副作用

帕金森病 (PD) 的特征是与致病性 α-突触核蛋白 (αSyn) 聚集体/寡聚体积累相关的黑质纹状体和皮质脑区的多巴胺能神经变性。LRRK2 过度活跃是 PD 中的疾病修饰治疗靶点。然而,LRRK2 抑制可能与外周效应有关,尽管临床后果尚不清楚。在这里,我们通过使用 GNE-7915(特异性脑渗透性 LRRK2 抑制剂)长期抑制 LRRK2,显着减少了小鼠纹状体中 αSyn 寡聚体的积累,而不会引起不良的外周效应。野生型 (WT) 小鼠血清和脑样本中的 GNE-7915 浓度在 1 小时达到峰值,在单次皮下 (100 mg/kg) 注射后 24 小时内逐渐下降。年轻 WT 和 LRRK2 R1441G的相同剂量突变小鼠显着抑制肺中的 LRRK2 激酶活性(Thr73-Rab10 和 Ser106-Rab12 磷酸化),注射后 72 小时消散。14 个月大的突变小鼠每周两次注射 GNE-7915,持续 18 周(相当于约 13 人年)表现出纹状体 αSyn 寡聚体和皮质 pSer129-αSyn 水平降低,这与抑制脑和肺中的 LRRK2 过度活跃至 WT 水平相关. 没有 GNE-7915 治疗的小鼠死亡率或发病率增加。与急性高剂量 LRRK2 抑制剂肺和肾脏异常的报道不同,我们的 GNE-7915 治疗的小鼠在 II 型肺细胞中没有表现出肿胀的层状体或在肾脏中出现异常空泡形成。肺、肾和肝的功能和组织病理学评估,包括全身体积描记法、尿白蛋白-肌酐比 (ACR)、长期 GNE-7915 治疗后,血清丙氨酸氨基转移酶 (ALT) 和血清白细胞介素 6(炎症标志物)未发现异常。将突变型 LRRK2 超激酶活性长期抑制到生理水平是一种有效且安全的疾病缓解疗法,可改善 PD 中的突触核蛋白病。

更新日期:2022-09-10
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