LRRK2 secretion in exosomes is regulated by 14-3-3
| Autor: | Elpida Tsika, Rita M. Cowell, James A. Mobley, Tong Ye, Mark S. Moehle, Darren J. Moore, Dongquan Chen, Kyle B. Fraser, Gene P. Siegal, Andrew B. West, Philip J. Webber, Kyoko Kojima, Jeri Y. Williams, Talene A. Yacoubian, João Paulo Lima Daher, Robert A. Galemmo, Terje Dokland, Carrie A. Stewart, David G. Standaert |
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| Předmět: |
Male
Endocytic cycle Protein Serine-Threonine Kinases Biology Exosomes Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Models Biological Exosome Mice Genetics Extracellular Animals Humans Secretion Kidney Tubules Collecting Molecular Biology Genetics (clinical) Mice Knockout Neurons Kinase Macrophages Epithelial Cells Articles General Medicine LRRK2 Microvesicles Rats Transport protein Cell biology nervous system diseases Protein Transport 14-3-3 Proteins Mutation Rats Transgenic Protein Binding |
| Popis: | Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset Parkinson's disease (PD). Emerging evidence suggests a role for LRRK2 in the endocytic pathway. Here, we show that LRRK2 is released in extracellular microvesicles (i.e. exosomes) from cells that natively express LRRK2. LRRK2 localizes to collecting duct epithelial cells in the kidney that actively secrete exosomes into urine. Purified urinary exosomes contain LRRK2 protein that is both dimerized and phosphorylated. We provide a quantitative proteomic profile of 1673 proteins in urinary exosomes and find that known LRRK2 interactors including 14-3-3 are some of the most abundant exosome proteins. Disruption of the 14-3-3 LRRK2 interaction with a 14-3-3 inhibitor or through acute LRRK2 kinase inhibition potently blocks LRRK2 release in exosomes, but familial mutations in LRRK2 had no effect on secretion. LRRK2 levels were overall comparable but highly variable in urinary exosomes derived from PD cases and age-matched controls, although very high LRRK2 levels were detected in some PD affected cases. We further characterized LRRK2 exosome release in neurons and macrophages in culture, and found that LRRK2-positive exosomes circulate in cerebral spinal fluid (CSF). Together, these results define a pathway for LRRK2 extracellular release, clarify one function of the LRRK2 14-3-3 interaction and provide a foundation for utilization of LRRK2 as a biomarker in clinical trials. |
| Databáze: | OpenAIRE |
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