scholarly journals LRRK2 GTPase dysfunction in the pathogenesis of Parkinson's disease

2012 ◽  
Vol 40 (5) ◽  
pp. 1074-1079 ◽  
Author(s):  
Yulan Xiong ◽  
Valina L. Dawson ◽  
Ted M. Dawson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Interaction ◽  
Kinase Activity ◽  
Present Review ◽  
Signalling Pathways ◽  
Gtpase Activity ◽  
Leucine Rich Repeat ◽  
Protein Protein Interaction ◽  
Interaction Domains

Mutations in the LRRK2 (leucine-rich repeat kinase 2) gene are the most frequent genetic cause of PD (Parkinson's disease), and these mutations play important roles in sporadic PD. The LRRK2 protein contains GTPase and kinase domains and several protein–protein interaction domains. The kinase and GTPase activity of LRRK2 seem to be important in regulating LRRK2-dependent cellular signalling pathways. LRRK2's GTPase and kinase domains may reciprocally regulate each other to direct LRRK2's ultimate function. Although most LRRK2 investigations are centred on LRRK2's kinase activity, the present review focuses on the function of LRRK2's GTPase activity in LRRK2 physiology and pathophysiology.

scholarly journals Activation Mechanism of LRRK2 and Its Cellular Functions in Parkinson’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Katharina E. Rosenbusch ◽  
Arjan Kortholt
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Activation Mechanism ◽  
Leucine Rich Repeat ◽  
Cellular Functions ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
Interaction Domains ◽  
Effector Binding

Human LRRK2 (Leucine-Rich Repeat Kinase 2) has been associated with both familial and idiopathic Parkinson’s disease (PD). Although several LRRK2 mediated pathways and interaction partners have been identified, the cellular functions of LRRK2 and LRRK2 mediated progression of PD are still only partially understood. LRRK2 belongs to the group of Roco proteins which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), a kinase, and several protein-protein interaction domains. Roco proteins exhibit a complex activation mechanism involving intramolecular signaling, dimerization, and substrate/effector binding. Importantly, PD mutations in LRRK2 have been linked to a decreased GTPase and impaired kinase activity, thus providing putative therapeutic targets. To fully explore these potential targets it will be crucial to understand the function and identify the pathways responsible for LRRK2-linked PD. Here, we review the recent progress in elucidating the complex LRRK2 activation mechanism, describe the accumulating evidence that link LRRK2-mediated PD to mitochondrial dysfunction and aberrant autophagy, and discuss possible ways for therapeutically targeting LRRK2.

scholarly journals Finnish Parkinson’s disease study integrating protein-protein interaction network data with exome sequencing analysis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ari Siitonen ◽  
Laura Kytövuori ◽  
Mike A. Nalls ◽  
Raphael Gibbs ◽  
Dena G. Hernandez ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Exome Sequencing ◽  
Protein Interaction ◽  
Multiple Testing ◽  
Interaction Network ◽  
Polygenic Risk Score ◽  
Sequencing Analysis ◽  
Protein Protein Interaction ◽  
Small Effect Size

AbstractVariants associated with Parkinson’s disease (PD) have generally a small effect size and, therefore, large sample sizes or targeted analyses are required to detect significant associations in a whole exome sequencing (WES) study. Here, we used protein-protein interaction (PPI) information on 36 genes with established or suggested associations with PD to target the analysis of the WES data. We performed an association analysis on WES data from 439 Finnish PD subjects and 855 controls, and included a Finnish population cohort as the replication dataset with 60 PD subjects and 8214 controls. Single variant association (SVA) test in the discovery dataset yielded 11 candidate variants in seven genes, but the associations were not significant in the replication cohort after correction for multiple testing. Polygenic risk score using variants rs2230288 and rs2291312, however, was associated to PD with odds ratio of 2.7 (95% confidence interval 1.4–5.2; p < 2.56e-03). Furthermore, an analysis of the PPI network revealed enriched clusters of biological processes among established and candidate genes, and these functional networks were visualized in the study. We identified novel candidate variants for PD using a gene prioritization based on PPI information, and described why these variants may be involved in the pathogenesis of PD.

scholarly journals 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization

2010 ◽  
Vol 430 (3) ◽  
pp. 393-404 ◽  
Author(s):  
R. Jeremy Nichols ◽  
Nicolas Dzamko ◽  
Nicholas A. Morrice ◽  
David G. Campbell ◽  
Maria Deak ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Kinase ◽  
Inclusion Bodies ◽  
Kinase Activity ◽  
Protein Isoforms ◽  
Protein Kinase Activity ◽  
Leucine Rich Repeat ◽  
Pathogenic Mutations ◽  
Mouse Tissues

LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients, but still little is understood about how it is regulated or functions. In the present study we have demonstrated that 14-3-3 protein isoforms interact with LRRK2. Consistent with this, endogenous LRRK2 isolated from Swiss 3T3 cells or various mouse tissues is associated with endogenous 14-3-3 isoforms. We have established that 14-3-3 binding is mediated by phosphorylation of LRRK2 at two conserved residues (Ser910 and Ser935) located before the leucine-rich repeat domain. Our results suggests that mutation of Ser910 and/or Ser935 to disrupt 14-3-3 binding does not affect intrinsic protein kinase activity, but induces LRRK2 to accumulate within discrete cytoplasmic pools, perhaps resembling inclusion bodies. To investigate links between 14-3-3 binding and Parkinson's disease, we studied how 41 reported mutations of LRRK2 affected 14-3-3 binding and cellular localization. Strikingly, we found that five of the six most common pathogenic mutations (R1441C, R1441G, R1441H, Y1699C and I2020T) display markedly reduced phosphorylation of Ser910/Ser935 thereby disrupting interaction with 14-3-3. We have also demonstrated that Ser910/Ser935 phosphorylation and 14-3-3 binding to endogenous LRRK2 is significantly reduced in tissues of homozygous LRRK2(R1441C) knock-in mice. Consistent with 14-3-3 regulating localization, all of the common pathogenic mutations displaying reduced 14-3-3-binding accumulated within inclusion bodies. We also found that three of the 41 LRRK2 mutations analysed displayed elevated protein kinase activity (R1728H, ~2-fold; G2019S, ~3-fold; and T2031S, ~4-fold). These results provide the first evidence suggesting that 14-3-3 regulates LRRK2 and that disruption of the interaction of LRRK2 with 14-3-3 may be linked to Parkinson's disease.

scholarly journals From The Cover: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity

2005 ◽  
Vol 102 (46) ◽  
pp. 16842-16847 ◽  
Author(s):  
A. B. West ◽  
D. J. Moore ◽  
S. Biskup ◽  
A. Bugayenko ◽  
W. W. Smith ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Leucine Rich Repeat
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