Role of LRRK2 kinase activity in the pathogenesis of Parkinson's disease

2012 ◽  
Vol 40 (5) ◽  
pp. 1058-1062 ◽  
Author(s):  
Elisa Greggio
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Complex Molecule ◽  
Disease Onset ◽  
Missense Mutations ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

Interest in studying the biology of LRRK2 (leucine-rich repeat kinase 2) started in 2004 when missense mutations in the LRRK2 gene were linked to an inherited form of Parkinson's disease with clinical and pathological presentation resembling the sporadic syndrome. LRRK2 is a complex molecule containing domains implicated in protein interactions, as well as kinase and GTPase activities. The observation that the common G2019S mutation increases kinase activity in vitro suggests that altered phosphorylation of LRRK2 targets may have pathological outcomes. Given that protein kinases are ideal targets for drug therapies, much effort has been directed at understanding the role of LRRK2 kinase activity on disease onset. However, no clear physiological substrates have been identified to date, indicating that much research is still needed to fully understand the signalling pathways orchestrated by LRRK2 and deregulated under pathological conditions.

scholarly journals LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniel Ysselstein ◽  
Maria Nguyen ◽  
Tiffany J. Young ◽  
Alex Severino ◽  
Michael Schwake ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Kinase Activity ◽  
Alpha Synuclein ◽  
Negative Regulator ◽  
Mutant Lrrk2 ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

AbstractMutations in LRRK2 and GBA1 are common genetic risk factors for Parkinson’s disease (PD) and major efforts are underway to develop new therapeutics that target LRRK2 or glucocerebrosidase (GCase). Here we describe a mechanistic and therapeutic convergence of LRRK2 and GCase in neurons derived from patients with PD. We find that GCase activity was reduced in dopaminergic (DA) neurons derived from PD patients with LRRK2 mutations. Inhibition of LRRK2 kinase activity results in increased GCase activity in DA neurons with either LRRK2 or GBA1 mutations. This increase is sufficient to partially rescue accumulation of oxidized dopamine and alpha-synuclein in PD patient neurons. We have identified the LRRK2 substrate Rab10 as a key mediator of LRRK2 regulation of GCase activity. Together, these results suggest an important role of mutant LRRK2 as a negative regulator of lysosomal GCase activity.

scholarly journals Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Cell Research ◽  
2019 ◽  
Vol 29 (4) ◽  
pp. 313-329 ◽  
Author(s):  
Adam Schaffner ◽  
Xianting Li ◽  
Yacob Gomez-Llorente ◽  
Emmanouela Leandrou ◽  
Anna Memou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Vitamin B12 ◽  
Kinase Activity ◽  
Allosteric Regulation ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

scholarly journals The activities of LRRK2 and GCase are positively correlated in clinical biospecimens and experimental models of Parkinson’s disease

2021 ◽  
Author(s):  
Maria Kedariti ◽  
Emanuele Frattini ◽  
Pascale Baden ◽  
Susanna Cogo ◽  
Laura Civiero ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Experimental Models ◽  
Cellular Functions ◽  
Gene Encoding ◽  
Cellular Models ◽  
Lrrk2 Kinase ◽  
The Impact ◽  
Lrrk2 Kinase Activity

AbstractLRRK2 is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways and vesicle trafficking. Mutations in LRRK2 cause autosomal dominant forms of Parkinson’s disease (PD). Heterozygous mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we investigated GCase levels and activity in LRRK2 G2019S knockin mice, in clinical biospecimens from PD patients carrying this mutation and in patient-derived cellular models. In these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase.

scholarly journals Discovery of catalytically active orthologues of the Parkinson's disease kinase PINK1: analysis of substrate specificity and impact of mutations

Open Biology ◽  
2011 ◽  
Vol 1 (3) ◽  
pp. 110012 ◽  
Author(s):  
Helen I. Woodroof ◽  
Joe H. Pogson ◽  
Mike Begley ◽  
Lewis C. Cantley ◽  
Maria Deak ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substrate Specificity ◽  
Kinase Activity ◽  
Phosphorylation Site ◽  
Kinase Domain ◽  
Missense Mutations ◽  
Pediculus Humanus ◽  
Tensin Homolog

Missense mutations of the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) gene cause autosomal-recessive Parkinson's disease. To date, little is known about the intrinsic catalytic properties of PINK1 since the human enzyme displays such low kinase activity in vitro . We have discovered that, in contrast to mammalian PINK1, insect orthologues of PINK1 we have investigated—namely Drosophila melanogaster (dPINK1) , Tribolium castaneum (TcPINK1) and Pediculus humanus corporis (PhcPINK1)—are active as judged by their ability to phosphorylate the generic substrate myelin basic protein. We have exploited the most active orthologue, TcPINK1, to assess its substrate specificity and elaborated a peptide substrate (PINKtide, KKWIpYRRSPRRR) that can be employed to quantify PINK1 kinase activity. Analysis of PINKtide variants reveal that PINK1 phosphorylates serine or threonine, but not tyrosine, and we show that PINK1 exhibits a preference for a proline at the +1 position relative to the phosphorylation site. We have also, for the first time, been able to investigate the effect of Parkinson's disease-associated PINK1 missense mutations, and found that nearly all those located within the kinase domain, as well as the C-terminal non-catalytic region, markedly suppress kinase activity. This emphasizes the crucial importance of PINK1 kinase activity in preventing the development of Parkinson's disease. Our findings will aid future studies aimed at understanding how the activity of PINK1 is regulated and the identification of physiological substrates.

scholarly journals Pathogenic mutations in LRRK2 sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

2020 ◽  
Author(s):  
Adamantios Mamais ◽  
Natalie Landeck ◽  
Rebekah G. Langston ◽  
Luis Bonet-Ponce ◽  
Nathan Smith ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Kinase Activity ◽  
Small Gtpase ◽  
Kinase Substrate ◽  
Lrrk2 Kinase ◽  
Effect Of Pd ◽  
Lrrk2 Kinase Activity

AbstractMutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson’s disease (PD) while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a are poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a into lysosomes in cells while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive accumulation of endocytosed transferrin into Rab8a-positive lysosomes leading to a dysregulation of iron transport. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in post-mortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

scholarly journals A High-Throughput Screen to Identify LRRK2 Kinase Inhibitors for the Treatment of Parkinson’s Disease Using RapidFire Mass Spectrometry

2015 ◽  
Vol 21 (2) ◽  
pp. 145-155 ◽  
Author(s):  
Melanie Leveridge ◽  
Lee Collier ◽  
Colin Edge ◽  
Phil Hardwicke ◽  
Bill Leavens ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Throughput ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Kinase Domain ◽  
Label Free ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

LRRK2 is a large multidomain protein containing two functional enzymatic domains: a GTPase domain and a protein kinase domain. Dominant coding mutations in the LRRK2 protein are associated with Parkinson’s disease (PD). Among such pathogenic mutations, Gly2019Ser mutation in the LRRK2 kinase domain is the most frequent cause of familial PD in Caucasians and is also found in some apparently sporadic PD cases. This mutation results in 2- to 3-fold elevated LRRK2 kinase activity compared with wild type, providing a clear clinical hypothesis for the application of kinase inhibitors in the treatment of this disease. To date, reported screening assays for LRRK2 have been based on detection of labeled adenosine triphosphate and adenosine diphosphate or on antibody-based detection of phosphorylation events. While these assays do offer a high-throughput method of monitoring LRRK2 kinase activity, they are prone to interference from autofluorescent compounds and nonspecific events. Here we describe a label-free assay for LRRK2 kinase activity using the RapidFire mass spectrometry system. This assay format was found to be highly robust and enabled a screen of 100,000 lead-like small molecules. The assay successfully identified a number of known LRRK2 chemotypes that met stringent physicochemical criteria.

scholarly journals P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity

2018 ◽  
Vol 475 (7) ◽  
pp. 1271-1293 ◽  
Author(s):  
Alexia F. Kalogeropulou ◽  
Jing Zhao ◽  
Marc F. Bolliger ◽  
Anna Memou ◽  
Shreya Narasimha ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Rab Proteins ◽  
Missense Mutations ◽  
Leucine Rich Repeat ◽  
Lrrk2 Gene ◽  
Ubiquitin Binding Domain ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity ◽  
In Cells

Autosomal-dominant, missense mutations in the leucine-rich repeat protein kinase 2 (LRRK2) gene are the most common genetic predisposition to develop Parkinson's disease (PD). LRRK2 kinase activity is increased in several pathogenic mutations (N1437H, R1441C/G/H, Y1699C, G2019S), implicating hyperphosphorylation of a substrate in the pathogenesis of the disease. Identification of the downstream targets of LRRK2 is a crucial endeavor in the field to understand LRRK2 pathway dysfunction in the disease. We have identified the signaling adapter protein p62/SQSTM1 as a novel endogenous interacting partner and a substrate of LRRK2. Using mass spectrometry and phospho-specific antibodies, we found that LRRK2 phosphorylates p62 on Thr138 in vitro and in cells. We found that the pathogenic LRRK2 PD-associated mutations (N1437H, R1441C/G/H, Y1699C, G2019S) increase phosphorylation of p62 similar to previously reported substrate Rab proteins. Notably, we found that the pathogenic I2020T mutation and the risk factor mutation G2385R displayed decreased phosphorylation of p62. p62 phosphorylation by LRRK2 is blocked by treatment with selective LRRK2 inhibitors in cells. We also found that the amino-terminus of LRRK2 is crucial for optimal phosphorylation of Rab7L1 and p62 in cells. LRRK2 phosphorylation of Thr138 is dependent on a p62 functional ubiquitin-binding domain at its carboxy-terminus. Co-expression of p62 with LRRK2 G2019S increases the neurotoxicity of this mutation in a manner dependent on Thr138. p62 is an additional novel substrate of LRRK2 that regulates its toxic biology, reveals novel signaling nodes and can be used as a pharmacodynamic marker for LRRK2 kinase activity.

scholarly journals LRRK2 and the Endolysosomal System in Parkinson’s Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 1271-1291
Author(s):  
Madalynn L. Erb ◽  
Darren J. Moore
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Neuronal Damage ◽  
Distinct Cell Type ◽  
In Vivo Models ◽  
Network Maintenance ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant familial Parkinson’s disease (PD), with pathogenic mutations enhancing LRRK2 kinase activity. There is a growing body of evidence indicating that LRRK2 contributes to neuronal damage and pathology both in familial and sporadic PD, making it of particular interest for understanding the molecular pathways that underlie PD. Although LRRK2 has been extensively studied to date, our understanding of the seemingly diverse functions of LRRK2 throughout the cell remains incomplete. In this review, we discuss the functions of LRRK2 within the endolysosomal pathway. Endocytosis, vesicle trafficking pathways, and lysosomal degradation are commonly disrupted in many neurodegenerative diseases, including PD. Additionally, many PD-linked gene products function in these intersecting pathways, suggesting an important role for the endolysosomal system in maintaining protein homeostasis and neuronal health in PD. LRRK2 activity can regulate synaptic vesicle endocytosis, lysosomal function, Golgi network maintenance and sorting, vesicular trafficking and autophagy, with alterations in LRRK2 kinase activity serving to disrupt or regulate these pathways depending on the distinct cell type or model system. LRRK2 is critically regulated by at least two proteins in the endolysosomal pathway, Rab29 and VPS35, which may serve as master regulators of LRRK2 kinase activity. Investigating the function and regulation of LRRK2 in the endolysosomal pathway in diverse PD models, especially in vivo models, will provide critical insight into the cellular and molecular pathophysiological mechanisms driving PD and whether LRRK2 represents a viable drug target for disease-modification in familial and sporadic PD.

scholarly journals The industrial solvent trichloroethylene induces LRRK2 kinase activity and dopaminergic neurodegeneration in a rat model of Parkinson's disease

2021 ◽  
Vol 153 ◽  
pp. 105312
Author(s):  
Briana R. De Miranda ◽  
Sandra L. Castro ◽  
Emily M. Rocha ◽  
Christopher R. Bodle ◽  
Katrina E. Johnson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Kinase Activity ◽  
Dopaminergic Neurodegeneration ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity
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