Thursday, August 20, 2015

Fly models of Parkinson's disease used in two studies focused on LRKK2

Schreij AM, Chaineau M, Ruan W, Lin S, Barker PA, Fon EA, McPherson PS. LRRK2 localizes to endosomes and interacts with clathrin-light chains to limit Rac1 activation. EMBO Rep. 2015 Jan;16(1):79-86. PMID: 25427558; PMCID: PMC4304731.

From the abstract: "Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of dominant-inherited Parkinson's disease (PD), and yet we do not fully understand the physiological function(s) of LRRK2. Various components of the clathrin machinery have been recently found mutated in familial forms of PD. Here, we provide molecular insight into the association of LRRK2 with the clathrin machinery. We report that through its GTPase domain, LRRK2 binds directly to clathrin-light chains (CLCs). ... In Drosphila, a minimal rough eye phenotype caused by overexpression of Rac1, is dramatically enhanced by loss of function of CLC and LRRK2 homologues, confirming the importance of this pathway in vivo. Our data identify a new pathway in which CLCs function with LRRK2 to control Rac1 activation on endosomes, providing a new link between the clathrin machinery, the cytoskeleton and PD."

Lin CH, Li H, Lee YN, Cheng YJ, Wu RM, Chien CT. Lrrk regulates the dynamic profile of dendritic Golgi outposts through the golgin Lava lamp. J Cell Biol. 2015 Aug 3;210(3):471-83. PMID: 26216903; PMCID: PMC4523617.

From the abstract: "Constructing the dendritic arbor of neurons requires dynamic movements of Golgi outposts (GOPs), the prominent component in the dendritic secretory pathway. ... Here, we show that Leucine-rich repeat kinase (Lrrk), the Drosophila melanogaster homologue of Parkinson's disease-associated Lrrk2, regulates GOP dynamics in dendrites. ... Whereas overexpression of kinase-dead Lrrk caused dominant-negative effects on GOP dynamics, overexpression of the human LRRK2 mutant G2019S with augmented kinase activity promoted retrograde movement. Our study reveals a pathogenic pathway for LRRK2 mutations causing dendrite degeneration."

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