Perez-Abshana Laura Patricia, Mendivil-Perez Miguel, Velez-Pardo Carlos, Jimenez-Del-Rio Marlene
Neuroscience Research Group, Faculty of Medicine, Institute of Medical Research, University of Antioquia, University Research Headquarters, Calle 70 #52-21 and Calle 62#52-59, Building 1, Laboratory 411/412, Medellin, 050010, Colombia.
Faculty of Nursing, University of Antioquia, University Research Headquarters, Calle 70 #52-21 and Calle 62#52-59, Building 1, Laboratory 411/412, Medellin, 050010, Colombia.
Neuromolecular Med. 2025 May 21;27(1):42. doi: 10.1007/s12017-025-08864-y.
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder for which there are currently no curative therapies. Therefore, the need for innovative treatments for this illness is critical. The glucosylceramidase beta 1 (GBA1) and leucine-rich repeated kinase 2 (LRRK2) genes have been postulated as potential genetically defined drug targets. We report for the first time that the LRRK2 inhibitor PF-06447475 (PF-475) not only restores GCase enzyme activity, but also increases mitochondrial membrane potential, significantly decreases DJ-1 Cys106-SO, reduces lysosome accumulation, and diminishes cleaved caspase-3 (CC3) in GBA1 K198E fibroblasts. Furthermore, in addition to a significant reduction in p-Ser935 LRRK2 kinase, we found that PF-475 reduced p-Thr73 RAB 10 and p-Ser129 α-Syn in mutant skin fibroblasts. In addition, we found that the GCase activator GCA (NCGC00188758) increased GCase activity and decreased lysosomal accumulation, but did not affect p-Ser935 LRRK2, ∆Ψm, p-Ser129 α-Syn, DJ-1 Cys106-SO, or CC3 in K198E GBA1 fibroblasts. The GCase inhibitor conduritol-β-epoxide (CBE), used as an internal control, significantly reduced GCase and left the other pathological markers largely unaltered in GBA1 K198E, but reduced GCase and increased the accumulation of lysosomes only in WT GBA1 fibroblasts. Taken together, these results suggest that LRRK2 is a critical signaling kinase in the pathogenic mechanism associated with the lysosomal GBA1/GCase K198E variant. Our findings suggest that the use of LRRK2 inhibitors in PD patients with GBA1 mutations, such as K198E, may be effective in reversing GBA1/GCase deficiency, autophagy impairment, oxidative stress, and neuronal death.
帕金森病（PD）是一种慢性进行性神经退行性疾病，目前尚无治愈性疗法。因此，对这种疾病进行创新治疗的需求至关重要。葡萄糖神经酰胺酶β1（GBA1）和富含亮氨酸重复激酶2（LRRK2）基因已被假定为潜在的基因定义药物靶点。我们首次报告，LRRK2抑制剂PF - 06447475（PF - 475）不仅能恢复葡糖脑苷脂酶（GCase）活性，还能增加线粒体膜电位，显著降低DJ - 1 Cys106 - SO，减少溶酶体积累，并减少GBA1 K198E成纤维细胞中裂解的半胱天冬酶 - 3（CC3）。此外，除了显著降低p - Ser935 LRRK2激酶外，我们发现PF - 475还能降低突变皮肤成纤维细胞中p - Thr73 RAB 10和p - Ser129 α - 突触核蛋白。此外，我们发现GCase激活剂GCA（NCGC00188758）增加了GCase活性并减少了溶酶体积累，但不影响K198E GBA1成纤维细胞中的p - Ser935 LRRK2、线粒体膜电位（∆Ψm）、p - Ser129 α - 突触核蛋白、DJ - 1 Cys106 - SO或CC3。用作内部对照的GCase抑制剂conduritol - β - 环氧化物（CBE）显著降低了GCase，并且在GBA1 K198E中其他病理标志物基本未改变，但仅在野生型GBA1成纤维细胞中降低了GCase并增加了溶酶体积累。综上所述，这些结果表明LRRK2是与溶酶体GBA1 / GCase K198E变体相关的致病机制中的关键信号激酶。我们的研究结果表明，在携带GBA1突变（如K198E）的PD患者中使用LRRK2抑制剂可能有效地逆转GBA1 / GCase缺乏、自噬损伤、氧化应激和神经元死亡。
