Kluss Jillian H, Conti Melissa M, Kaganovich Alice, Beilina Aleksandra, Melrose Heather L, Cookson Mark R, Mamais Adamantios
1Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD USA.
2Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224 USA.
NPJ Parkinsons Dis. 2018 Apr 19;4:13. doi: 10.1038/s41531-018-0049-1. eCollection 2018.
Parkinson's disease-linked mutations in enhance the kinase activity of the protein, therefore targeting LRRK2 kinase activity is a promising therapeutic approach. Phosphorylation at S935 of LRRK2 and of its Rab GTPase substrates have proven very useful biomarkers to monitor its kinase activity. Complementary to these approaches autophosphorylation of LRRK2 can be used as a direct kinase activity readout but to date detection of autophosphorylation at endogenous levels in vivo has been limited. We developed a fractionation-based enrichment method to successfully detect endogenous S1292 LRRK2 autophosphorylation in mouse tissues and highlight S1292 as a physiological readout candidate for LRRK2 kinase activity in vivo.
与帕金森病相关的突变增强了该蛋白的激酶活性，因此靶向LRRK2激酶活性是一种很有前景的治疗方法。LRRK2在S935位点的磷酸化及其Rab GTPase底物已被证明是监测其激酶活性非常有用的生物标志物。作为这些方法的补充，LRRK2的自磷酸化可作为直接的激酶活性读数，但迄今为止，体内内源性水平自磷酸化的检测一直有限。我们开发了一种基于分级分离的富集方法，成功地检测了小鼠组织中内源性S1292位点的LRRK2自磷酸化，并将S1292突出显示为体内LRRK2激酶活性的生理读数候选位点。
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