Filippini Alice, Gennarelli Massimo, Russo Isabella
Genetics Unit, IRCCS Istituto Centro S. Giovanni di Dio, Fatebenefratelli, 25125 Brescia, Italy.
Biology and Genetics Unit, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
Biochem Soc Trans. 2021 Jun 30;49(3):1375-1384. doi: 10.1042/BST20201092.
Missense mutations in the leucine-rich repeat kinase-2 (LRRK2) gene represent the most common cause of autosomal dominant Parkinson's disease (PD). In the years LRRK2 has been associated with several organelles and related pathways in cell. However, despite the significant amount of research done in the past decade, the contribution of LRRK2 mutations to PD pathogenesis remains unknown. Growing evidence highlights that LRRK2 controls multiple processes in brain immune cells, microglia and astrocytes, and suggests that deregulated LRRK2 activity in these cells, due to gene mutation, might be directly associated with pathological mechanisms underlying PD. In this brief review, we recapitulate and update the last LRRK2 functions dissected in microglia and astrocytes. Moreover, we discuss how dysfunctions of LRRK2-related pathways may impact glia physiology and their cross-talk with neurons, thus leading to neurodegeneration and progression of PD.
富含亮氨酸重复激酶2(LRRK2)基因的错义突变是常染色体显性帕金森病(PD)最常见的病因。多年来,LRRK2一直与细胞中的多种细胞器及相关通路有关。然而,尽管在过去十年中进行了大量研究,但LRRK2突变对PD发病机制的作用仍不清楚。越来越多的证据表明,LRRK2控制着脑免疫细胞、小胶质细胞和星形胶质细胞中的多个过程,并提示由于基因突变导致这些细胞中LRRK2活性失调,可能与PD潜在的病理机制直接相关。在这篇简短的综述中,我们总结并更新了最近在小胶质细胞和星形胶质细胞中解析出的LRRK2功能。此外,我们还讨论了LRRK2相关通路功能障碍如何影响胶质细胞生理学及其与神经元的相互作用,从而导致神经退行性变和PD的进展。