Gómez-Suaga P, Fdez E, Fernández B, Martínez-Salvador M, Blanca Ramírez M, Madero-Pérez J, Rivero-Ríos P, Fuentes J M, Hilfiker S
Institute of Parasitology and Biomedicine "López-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
Departamento de Bioquímica y Biología Molecular y Genética, E. Enfermería y TO, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universidad de Extremadura, Cáceres, Spain.
Neuropharmacology. 2014 Oct;85:45-56. doi: 10.1016/j.neuropharm.2014.05.020. Epub 2014 May 24.
Mutations in LRRK2 (leucine-rich repeat kinase 2) are found associated with both sporadic and familial Parkinson's disease (PD). Pathogenic mutations are localized to the catalytic domains of LRRK2, including kinase and GTPase domains. Altered catalytic activity correlates with neurotoxicity, indicating that targeting those activities may provide clues as to novel therapeutic strategies for LRRK2-linked PD. However, the cellular readout of such altered catalytic activities remains largely unknown. Recent cell biological studies have started to highlight possible early cellular events which are altered in the presence of pathogenic LRRK2 and may ultimately lead to neuronal demise, and these studies link altered LRRK2 function to various abnormal endolysosomal vesicular trafficking events. This review examines our current knowledge of LRRK2 neurobiology and how pathogenic mutations may lead to neurodegeneration in PD.
富亮氨酸重复激酶2（LRRK2）的突变与散发性和家族性帕金森病（PD）均有关联。致病性突变定位于LRRK2的催化结构域，包括激酶结构域和GTP酶结构域。催化活性的改变与神经毒性相关，这表明针对这些活性可能为LRRK2相关帕金森病的新治疗策略提供线索。然而，这种催化活性改变的细胞表现仍 largely未知。最近的细胞生物学研究已开始突显在致病性LRRK2存在时可能发生改变并最终可能导致神经元死亡的早期细胞事件，并且这些研究将LRRK2功能改变与各种异常的内溶酶体囊泡运输事件联系起来。本综述探讨了我们目前对LRRK2神经生物学的了解以及致病性突变可能如何导致帕金森病中的神经退行性变。
