Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain

被引：50

作者：

Civiero, Laura ^{[1
]}

Cirnaru, Maria Daniela ^{[2
]}

Beilina, Alexandra ^{[3
]}

Rodella, Umberto ^{[1
,4
]}

Russo, Isabella ^{[1
]}

Belluzzi, Elisa ^{[1
]}

Lobbestael, Evy ^{[4
]}

Reyniers, Lauran ^{[4
]}

Hondhamuni, Geshanthi ^{[5
]}

Lewis, Patrick A. ^{[6
,7
]}

Van den Haute, Chris ^{[4
,8
]}

Baekelandt, Veerle ^{[4
]}

Bandopadhyay, Rina ^{[5
]}

Bubacco, Luigi ^{[1
]}

Piccoli, Giovanni ^{[2
]}

Cookson, Mark R. ^{[3
]}

Taymans, Jean-Marc ^{[4
]}

Greggio, Elisa ^{[1
]}

机构：

[1] Univ Padua, Dept Biol, I-35131 Padua, Italy

[2] Univ Vita Salute San Raffaele, Milan, Italy

[3] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[4] Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, Leuven, Belgium

[5] UCL, Dept Mol Neurosci, Reta Lila Weston Inst Neurol Studies, Inst Neurol, London, England

[6] Univ Reading, Sch Pharm, Reading, Berks, England

[7] UCL, Inst Neurol, Dept Mol Neurosci, London, England

[8] Katholieke Univ Leuven, Leuven Viral Vector Core, Leuven, Belgium

来源：

JOURNAL OF NEUROCHEMISTRY | 2015年 / 135卷 / 06期

基金：

英国惠康基金;

关键词：

LRRK2; neurodegeneration; neuronal cytoskeleton; p21-activated kinases; Parkinson's disease; DOPAMINERGIC-NEURONS; ACTIN CYTOSKELETON; 14-3-3; BINDING; LRRK2; CONTROLS; GTP-BINDING; DISEASE; PHOSPHORYLATION; INHIBITION; MUTATIONS; PATHWAY;

D O I：

10.1111/jnc.13369

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Leucine-rich repeat kinase 2 (LRRK2) is a causative gene for Parkinson's disease, but the physiological function and the mechanism(s) by which the cellular activity of LRRK2 is regulated are poorly understood. Here, we identified p21-activated kinase 6 (PAK6) as a novel interactor of the GTPase/ROC domain of LRRK2. p21-activated kinases are serine-threonine kinases that serve as targets for the small GTP binding proteins Cdc42 and Rac1 and have been implicated in different morphogenetic processes through remodeling of the actin cytoskeleton such as synapse formation and neuritogenesis. Using an in vivo neuromorphology assay, we show that PAK6 is a positive regulator of neurite outgrowth and that LRRK2 is required for this function. Analyses of post-mortem brain tissue from idiopathic and LRRK2 G2019S carriers reveal an increase in PAK6 activation state, whereas knock-out LRRK2mice display reduced PAK6 activation and phosphorylation of PAK6 substrates. Taken together, these results support a critical role of LRRK2 GTPase domain in cytoskeletal dynamics in vivo through the novel interactor PAK6, and provide a valuable platform to unravel the mechanism underlying LRRK2-mediated pathophysiology.

引用

页码：1242 / 1256

页数：15

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