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PLoS One. 2009 Dec 24;4(12):e8463. doi: 10.1371/journal.pone.0008463.

The WD40 domain is required for LRRK2 neurotoxicity.

Author information

1
Department of Neurology, Columbia University Medical Center, New York, New York, United States of America.

Abstract

BACKGROUND:

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD). LRRK2 contains an "enzymatic core" composed of GTPase and kinase domains that is flanked by leucine-rich repeat (LRR) and WD40 protein-protein interaction domains. While kinase activity and GTP-binding have both been implicated in LRRK2 neurotoxicity, the potential role of other LRRK2 domains has not been as extensively explored.

PRINCIPAL FINDINGS:

We demonstrate that LRRK2 normally exists in a dimeric complex, and that removing the WD40 domain prevents complex formation and autophosphorylation. Moreover, loss of the WD40 domain completely blocks the neurotoxicity of multiple LRRK2 PD mutations.

CONCLUSION:

These findings suggest that LRRK2 dimerization and autophosphorylation may be required for the neurotoxicity of LRRK2 PD mutations and highlight a potential role for the WD40 domain in the mechanism of LRRK2-mediated cell death.

PMID:
20041156
PMCID:
PMC2794542
DOI:
10.1371/journal.pone.0008463
[Indexed for MEDLINE]
Free PMC Article

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