scholarly journals L'RRK de Triomphe: a solution for LRRK2 GTPase activity?

2016 ◽  
Vol 44 (6) ◽  
pp. 1625-1634 ◽  
Author(s):  
Jonathon Nixon-Abell ◽  
Daniel C. Berwick ◽  
Kirsten Harvey
Keyword(s):  
Parkinson’S Disease ◽  
Normal Function ◽  
Gtpase Activity ◽  
Leucine Rich Repeat ◽  
Gtpase Domain ◽  
Working Model ◽  
Pathogenic Mutations ◽  
Central Protein ◽  
Data Point ◽  
New Treatments

Leucine-rich repeat kinase 2 (LRRK2) is a central protein in the pathogenesis of Parkinson's disease (PD), yet its normal function has proved stubbornly hard to elucidate. Even though it remains unclear how pathogenic mutations affect LRRK2 to cause PD, recent findings provide increasing cause for optimism. We summarise here the developing consensus over the effect of pathogenic mutations in the Ras of complex proteins and C-terminal of Roc domains on LRRK2 GTPase activity. This body of work has been greatly reinforced by our own study of the protective R1398H variant contained within the LRRK2 GTPase domain. Collectively, data point towards the pathogenicity of GTP-bound LRRK2 and strengthen a working model for LRRK2 GTPase function as a GTPase activated by dimerisation. Together with the identification of the protective R1398H variant as a valuable control for pathogenic mutations, we have no doubt that these triumphs for the LRRK2 field will accelerate research towards resolving LRRK2 function and towards new treatments for 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 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 The role of (auto)-phosphorylation in the complex activation mechanism of LRRK2

2018 ◽  
Vol 399 (7) ◽  
pp. 643-647 ◽  
Author(s):  
Panagiotis S. Athanasopoulos ◽  
Rolf Heumann ◽  
Arjan Kortholt
Keyword(s):  
Parkinson’S Disease ◽  
Late Onset ◽  
Kinase Domain ◽  
Activation Mechanism ◽  
Phosphorylation Sites ◽  
Gtpase Activity ◽  
Leucine Rich Repeat ◽  
Large Protein ◽  
N Terminus

AbstractMutations in human leucine-rich-repeat kinase 2 (LRRK2) have been found to be the most frequent cause of late-onset Parkinson’s Disease (PD). LRRK2 is a large protein with two enzymatic domains, a GTPase and a kinase domain. A cluster of (auto)-phosphorylation sites within the N-terminus of LRRK2 have been shown to be crucial for the localization of LRRK2 and is important for PD pathogenesis. In addition, phosphorylation of sites within the G-domain of the protein affect GTPase activity. Here we discuss the role of these (auto)-phosphorylation sites of LRRK2 and their regulation by phosphatases and upstream kinases.

Deciphering the function of leucine-rich repeat kinase 2 and targeting its dysfunction in disease1

2012 ◽  
Vol 40 (5) ◽  
pp. 1039-1041 ◽  
Author(s):  
Patrick A. Lewis ◽  
Dario R. Alessi
Keyword(s):  
Parkinson’S Disease ◽  
Inflammatory Bowel Disease ◽  
Parkinson's Disease ◽  
Bowel Disease ◽  
Therapeutic Target ◽  
Unknown Function ◽  
Normal Function ◽  
Human Diseases ◽  
Leucine Rich Repeat ◽  
Inflammatory Bowel

LRRK2 (leucine-rich repeat kinase 2) is a gene of unknown function that has been linked to a number a human diseases, including PD (Parkinson's disease), IBD (inflammatory bowel disease), leprosy and cancer. The papers from the LRRK2: Function and Dysfunction meeting in this issue of Biochemical Society Transactions explore our growing knowledge of LRRK2's normal function, the role that it plays in disease and emerging strategies to exploit LRRK2 as a therapeutic target.

A link between LRRK2, autophagy and NAADP-mediated endolysosomal calcium signalling

2012 ◽  
Vol 40 (5) ◽  
pp. 1140-1146 ◽  
Author(s):  
Patricia Gómez-Suaga ◽  
Grant C. Churchill ◽  
Sandip Patel ◽  
Sabine Hilfiker
Keyword(s):  
Parkinson’S Disease ◽  
Nicotinic Acid ◽  
Kinase Activity ◽  
Current Knowledge ◽  
Calcium Signalling ◽  
Therapeutic Strategies ◽  
Leucine Rich Repeat ◽  
Significant Component ◽  
Pathogenic Mutations ◽  
Ca2 Channels

Mutations in LRRK2 (leucine-rich repeat kinase 2) represent a significant component of both sporadic and familial PD (Parkinson's disease). Pathogenic mutations cluster in the enzymatic domains of LRRK2, and kinase activity seems to correlate with cytotoxicity, suggesting the possibility of kinase-based therapeutic strategies for LRRK2-associated PD. Apart from cytotoxicity, changes in autophagy have consistently been observed upon overexpression of mutant, or knockdown of endogenous, LRRK2. However, delineating the precise mechanism(s) by which LRRK2 regulates autophagy has been difficult. Recent data suggest a mechanism involving late steps in autophagic–lysosomal clearance in a manner dependent on NAADP (nicotinic acid–adenine dinucleotide phosphate)-sensitive lysosomal Ca2+ channels. In the present paper, we review our current knowledge of the link between LRRK2 and autophagic–lysosomal clearance, including regulation of Ca2+-dependent events involving NAADP.

scholarly journals A revised 1.6 Å structure of the GTPase domain of the Parkinson’s disease-associated protein LRRK2 provides insights into mechanisms

2019 ◽  
Author(s):  
Chun-Xiang Wu ◽  
Jingling Liao ◽  
Yangshin Park ◽  
Neo C. Hoang ◽  
Victoria A. Engel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Conformational Dynamics ◽  
Normal Function ◽  
Gtpase Domain ◽  
Dimer Interface ◽  
Switch Regions ◽  
Π Stacking Interaction ◽  
The Common ◽  
Familial Parkinson’S Disease

Leucine-rich repeat kinase 2 (LRRK2) is a large 286 kDa multi-domain protein whose mutation is a common cause of Parkinson’s disease (PD). One of the common sites of familial PD-associated mutations occurs at residue Arg-1441 in the GTPase domain of LRRK2. Previously, we reported that the PD-associated mutation R1441H impairs the catalytic activity of the GTPase domain thereby traps it in a persistently "on" state. More recently, we reported that the GTPase domain of LRRK2 exists in a dynamic dimer-monomer equilibrium where GTP binding shifts it to the monomeric conformation while GDP binding shifts it back to the dimeric state. We also reported that all of the PD-associated mutations at Arg-1441, including R1441H, R1441C, and R1441G, impair the nucleotide-dependent dimer-monomer conformational dynamics of the GTPase domain. However, the mechanism of this nucleotide-dependent conformational dynamics and how it is impaired by the mutations at residue Arg-1441 remained unclear. Here, we report a 1.6 Å crystal structure of the GTPase domain of LRRK2. Our structure has revealed a dynamic switch region that can be differentially regulated by GTP and GDP binding. This nucleotide-dependent regulation is impaired when residue Arg-1441 is substituted with the PD-associated mutations due to the loss of its exquisite interactions consisting of two hydrogen bonds and a π-stacking interaction at the dimer interface.Significance StatementMutations in LRRK2 are associated with familial Parkinson’s disease, so understanding its mechanism of actions and how they are changed by the disease-associated mutations is important for developing therapeutic strategies. This paper describes an atomic structure of the G-domain of LRRK2 revealing that the conformational dynamics of the switch regions are potentially important for its normal function. It further shows that a disease-associated mutation could lock the G domain in a persistently active-like conformation, thus perturbing its normal function.

scholarly journals Effect of a Leucine-rich Repeat Kinase 2 Variant on Motor and Non-motor Symptoms in Chinese Parkinson’s Disease Patients

2016 ◽  
Vol 7 (3) ◽  
pp. 230 ◽  
Author(s):  
Qian Sun ◽  
Tian Wang ◽  
Tian-Fang Jiang ◽  
Pei Huang ◽  
Dun-Hui Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Symptoms ◽  
Leucine Rich Repeat ◽  
Non Motor Symptoms
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