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Hum Mol Genet. 2014 Aug 15;23(16):4201-14. doi: 10.1093/hmg/ddu138. Epub 2014 Mar 27.

Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy.

Author information

1
Center for Neurologic Diseases, Harvard Medical School, Boston, MA 02115, USA and Brigham and Women's Hospital, Boston, MA 02115, USA.
2
Brigham and Women's Hospital, Boston, MA 02115, USA.
3
Center for Neurologic Diseases, Harvard Medical School, Boston, MA 02115, USA and Brigham and Women's Hospital, Boston, MA 02115, USA mlavoie@rics.bwh.harvard.edu.

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and idiopathic Parkinson's disease. However, the mechanisms for activating its physiological function are not known, hindering identification of the biological role of endogenous LRRK2. The recent discovery that LRRK2 is highly expressed in cells of the innate immune system and genetic association is a risk factor for autoimmune disorders implies an important role for LRRK2 in pathology outside of the central nervous system. Thus, an examination of endogenous LRRK2 in immune cells could provide insight into the protein's function. Here, we establish that stimulation of specific Toll-like receptors results in a complex biochemical activation of endogenous LRRK2, with early phosphorylation of LRRK2 preceding its dimerization and membrane translocation. Membrane-associated LRRK2 co-localized to autophagosome membranes following either TLR4 stimulation or mTOR inhibition with rapamycin. Silencing of endogenous LRRK2 expression resulted in deficits in the induction of autophagy and clearance of a well-described macroautophagy substrate, demonstrating the critical role of endogenous LRRK2 in regulating autophagy. Inhibition of LRRK2 kinase activity also reduced autophagic degradation and suggested the importance of the kinase domain in the regulation of autophagy. Our results demonstrate a well-orchestrated series of biochemical events involved in the activation of LRRK2 important to its physiological function. With similarities observed across multiple cell types and stimuli, these findings are likely relevant in all cell types that natively express endogenous LRRK2, and provide insights into LRRK2 function and its role in human disease.

PMID:
24682598
PMCID:
PMC4103671
DOI:
10.1093/hmg/ddu138
[Indexed for MEDLINE]
Free PMC Article

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