Marchand Antoine, Drouyer Matthieu, Sarchione Alessia, Chartier-Harlin Marie-Christine, Taymans Jean-Marc
University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France.
Inserm, UMR-S 1172, Team "Brain Biology and Chemistry", Lille, France.
Front Neurosci. 2020 Jun 16;14:527. doi: 10.3389/fnins.2020.00527. eCollection 2020.
Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene are linked to autosomal dominant Parkinson's disease (PD), and genetic variations at the LRRK2 locus are associated with an increased risk for sporadic PD. This gene encodes a kinase that is physiologically multiphosphorylated, including clusters of both heterologous phosphorylation and autophosphorylation sites. Several pieces of evidence indicate that LRRK2's phosphorylation is important for its pathological and physiological functioning. These include a reduced LRRK2 heterologous phosphorylation in PD brains or after pharmacological inhibition of LRRK2 kinase activity as well as the appearance of subcellular LRRK2 accumulations when this protein is dephosphorylated at heterologous phosphosites. Nevertheless, the regulatory mechanisms governing LRRK2 phosphorylation levels and the cellular consequences of changes in LRRK2 phosphorylation remain incompletely understood. In this review, we present current knowledge on LRRK2 phosphorylation, LRRK2 phosphoregulation, and how LRRK2 phosphorylation changes affect cellular processes that may ultimately be linked to PD mechanisms.
富含亮氨酸重复激酶2（LRRK2）基因的突变与常染色体显性帕金森病（PD）相关，并且LRRK2基因座处的基因变异与散发性PD风险增加有关。该基因编码一种在生理上会发生多磷酸化的激酶，包括异源磷酸化位点和自磷酸化位点簇。多项证据表明，LRRK2的磷酸化对其病理和生理功能很重要。这些证据包括在PD大脑中或在药理学上抑制LRRK2激酶活性后LRRK2异源磷酸化减少，以及当该蛋白在异源磷酸位点去磷酸化时亚细胞LRRK2积累的出现。然而，控制LRRK2磷酸化水平的调节机制以及LRRK2磷酸化变化的细胞后果仍未完全了解。在这篇综述中，我们介绍了关于LRRK2磷酸化、LRRK2磷酸调节以及LRRK2磷酸化变化如何影响可能最终与PD机制相关的细胞过程的当前知识。
