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The Journal of Neuroscience, November 4, 2009, 29(44):13971-13980; doi:10.1523/JNEUROSCI.3799-09.2009

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Neurobiology of Disease
Phosphorylation of Ezrin/Radixin/Moesin Proteins by LRRK2 Promotes the Rearrangement of Actin Cytoskeleton in Neuronal Morphogenesis

Loukia Parisiadou,¹ Chengsong Xie,¹ Hyun Jin Cho,¹ Xian Lin,¹ Xing-Long Gu,¹ Cai-Xia Long,¹ Evy Lobbestael,² Veerle Baekelandt,² Jean-Marc Taymans,² Lixin Sun,¹ and Huaibin Cai¹

¹Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, and ²Laboratory for Neurobiology and Gene Therapy, Division of Molecular Medicine, Department of Molecular and Cellular Medicine, Faculty of Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

Correspondence should be addressed to Huaibin Cai, Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A116, MSC 3707, 35 Convent Drive, Bethesda, MD 20892-3707. Email: caih{at}mail.nih.gov

Leucine-rich repeat kinase 2 (LRRK2) functions as a putative protein kinase of ezrin, radixin, and moesin (ERM) family proteins. A Parkinson's disease-related G2019S substitution in the kinase domain of LRRK2 further enhances the phosphorylation of ERM proteins. The phosphorylated ERM (pERM) proteins are restricted to the filopodia of growing neurites in which they tether filamentous actin (F-actin) to the cytoplasmic membrane and regulate the dynamics of filopodia protrusion. Here, we show that, in cultured neurons derived from LRRK2 G2019S transgenic mice, the number of pERM-positive and F-actin-enriched filopodia was significantly increased, and this correlates with the retardation of neurite outgrowth. Conversely, deletion of LRRK2, which lowered the pERM and F-actin contents in filopodia, promoted neurite outgrowth. Furthermore, inhibition of ERM phosphorylation or actin polymerization rescued the G2019S-dependent neuronal growth defects. These data support a model in which the G2019S mutation of LRRK2 causes a gain-of-function effect that perturbs the homeostasis of pERM and F-actin in sprouting neurites critical for neuronal morphogenesis.

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Received Aug. 4, 2009; accepted Sept. 2, 2009.

Correspondence should be addressed to Huaibin Cai, Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A116, MSC 3707, 35 Convent Drive, Bethesda, MD 20892-3707. Email: caih{at}mail.nih.gov

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LRRK2 localizes to filopodia

Javier Alegre-Abarrategui

J. Neurosci. Online, 11 Nov 2009 [Full text]

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