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EMBO J. 2014 Oct 16;33(20):2314-31. doi: 10.15252/embj.201487807. Epub 2014 Sep 8.

Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.

Author information

1
Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA.
2
Laboratory of Neurochemistry and Laboratory of Neurobiology National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
3
Bioinformatics Core, Laboratory of Neurogenetics National Institute on Aging, Bethesda, MD, USA.
4
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases National Institutes of Health, Bethesda, MD, USA Institute of Biophysics Chinese Academy of Sciences, Beijing, China zhihualiu@ibp.ac.cn caih@mail.nih.gov.
5
Transgenics Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health, Bethesda, MD, USA zhihualiu@ibp.ac.cn caih@mail.nih.gov.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been associated with Parkinson's disease (PD) and other disorders. However, its normal physiological functions and pathogenic properties remain elusive. Here we show that LRRK2 regulates the anterograde ER-Golgi transport through anchoring Sec16A at the endoplasmic reticulum exit sites (ERES). LRRK2 interacted and co-localized with Sec16A, a key protein in the formation of ERES. Lrrk2 depletion caused a dispersion of Sec16A from ERES and impaired ER export. In neurons, LRRK2 and Sec16A showed extensive co-localization at the dendritic ERES (dERES) that locally regulate the transport of proteins to the dendritic spines. A loss of Lrrk2 affected the association of Sec16A with dERES and impaired the activity-dependent targeting of glutamate receptors onto the cell/synapse surface. Furthermore, the PD-related LRRK2 R1441C missense mutation in the GTPase domain interfered with the interaction of LRRK2 with Sec16A and also affected ER-Golgi transport, while LRRK2 kinase activity was not required for these functions. Therefore, our findings reveal a new physiological function of LRRK2 in ER-Golgi transport, suggesting ERES dysfunction may contribute to the pathogenesis of PD.

KEYWORDS:

ER exit sites (ERES); ER–Golgi transport; Leucine‐rich repeat kinase 2 (LRRK2); Sec16A; dendritic ERES (dERES)

PMID:
25201882
PMCID:
PMC4253522
DOI:
10.15252/embj.201487807
[Indexed for MEDLINE]
Free PMC Article

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