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 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 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 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 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

scholarly journals The Parkinson’s disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase thatstimulates kinase activity

2007 ◽  
Vol 313 (16) ◽  
pp. 3658-3670 ◽  
Author(s):  
Luxuan Guo ◽  
Payal N. Gandhi ◽  
Wen Wang ◽  
Robert B. Petersen ◽  
Amy L. Wilson-Delfosse ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Leucine Rich Repeat

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 The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation

2012 ◽  
Vol 446 (1) ◽  
pp. 99-111 ◽  
Author(s):  
Iakov N. Rudenko ◽  
Alice Kaganovich ◽  
David N. Hauser ◽  
Aleksandra Beylina ◽  
Ruth Chia ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Missense Mutations ◽  
Leucine Rich Repeat ◽  
Loss Of Function ◽  
Partial Loss ◽  
G2019s Mutation ◽  
Enzymatic Function ◽  
C Terminus

Autosomal-dominant missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a common genetic cause of PD (Parkinson's disease). LRRK2 is a multidomain protein with kinase and GTPase activities. Dominant mutations are found in the domains that have these two enzyme activities, including the common G2019S mutation that increases kinase activity 2–3-fold. However, there is also a genetic variant in some populations, G2385R, that lies in a C-terminal WD40 domain of LRRK2 and acts as a risk factor for PD. In the present study we show that the G2385R mutation causes a partial loss of the kinase function of LRRK2 and deletion of the C-terminus completely abolishes kinase activity. This effect is strong enough to overcome the kinase-activating effects of the G2019S mutation in the kinase domain. Hsp90 (heat-shock protein of 90 kDa) has an increased affinity for the G2385R variant compared with WT (wild-type) LRRK2, and inhibition of the chaperone binding combined with proteasome inhibition leads to association of mutant LRRK2 with high molecular mass native fractions that probably represent proteasome degradation pathways. The loss-of-function of G2385R correlates with several cellular phenotypes that have been proposed to be kinase-dependent. These results suggest that the C-terminus of LRRK2 plays an important role in maintaining enzymatic function of the protein and that G2385R may be associated with PD in a way that is different from kinase-activating mutations. These results may be important in understanding the differing mechanism(s) by which mutations in LRRK2 act and may also have implications for therapeutic strategies for PD.

scholarly journals mTOR independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Claudia Manzoni ◽  
Adamantios Mamais ◽  
Sybille Dihanich ◽  
Marc P.M. Soutar ◽  
Helene Plun-Favreau ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Protein Phosphorylation ◽  
Kinase Activity ◽  
Central Component ◽  
Leucine Rich Repeat ◽  
Kinase Inhibition ◽  
Enzymatic Function ◽  
Lrrk2 Kinase ◽  
Pathway Regulation ◽  
Mtor Complex 1

Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to repression of autophagosome biogenesis and was thought to be exclusively dependent upon mTOR complex 1 kinase activity. In the present study, a novel regulation of Ser758 ULK1 phosphorylation is reported following prolonged inhibition of the Parkinson’s disease linked protein leucine rich repeat kinase 2 (LRRK2). Here, modulation of Ser758 ULK1 phosphorylation following LRRK2 inhibition is decoupled from the repression of autophagosome biogenesis and independent of mTOR complex 1 activity.

Targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson's disease

2019 ◽  
Vol 11 (15) ◽  
pp. 1953-1977 ◽  
Author(s):  
Sofia Domingos ◽  
Teresa Duarte ◽  
Lucília Saraiva ◽  
Rita C Guedes ◽  
Rui Moreira
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Leucine Rich Repeat ◽  
Serine Threonine Kinase ◽  
Drug Candidates ◽  
Cellular Processes ◽  
Pathogenic Variants ◽  
Lrrk2 Kinase ◽  
Relationship Of

Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase involved in multiple cellular processes and signaling pathways. LRRK2 mutations are associated with autosomal-inherited Parkinson's disease (PD), and evidence suggests that LRRK2 pathogenic variants generally increase kinase activity. Therefore, inhibition of LRRK2 kinase function is a promising therapeutic strategy for PD treatment. The search for drug-like molecules capable of reducing LRRK2 kinase activity in PD led to the design of selective LRRK2 inhibitors predicted to be within the CNS drug-like space. This review highlights the journey that translates chemical tools for interrogating the role of LRRK2 in PD into promising drug candidates, addressing the challenges in discovering selective and brain-penetrant LRRK2 modulators and exploring the structure–activity relationship of distinct LRRK2 inhibitors.

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