scholarly journals New Light Shed on Leucine-Rich Repeat Kinase 2 (LRRK2) Kinase Inhibitors in Parkinson's Disease

2016 ◽  
Vol 3 (3) ◽  
pp. 241-242
Author(s):  
Diana A. Olszewska ◽  
Tim Lynch
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitors ◽  
Leucine Rich Repeat ◽  
Lrrk2 Kinase

scholarly journals From structure to ætiology: a new window on the biology of leucine-rich repeat kinase 2 and Parkinson's disease

2021 ◽  
Vol 478 (14) ◽  
pp. 2945-2951
Author(s):  
Susanne Herbst ◽  
Patrick A. Lewis
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitors ◽  
Leucine Rich Repeat ◽  
Large Size ◽  
Domain Organisation ◽  
Lrrk2 Kinase ◽  
Resolution Structure

Since the discovery of mutations in leucine-rich repeat kinase 2 (LRRK2) as an underlying genetic cause for the development of Parkinson's disease (PD) in 2004 (Neuron 44, 601–607; Neuron 44, 595–600), and subsequent efforts to develop LRRK2 kinase inhibitors as a therapy for Parkinson's (Expert Opin. Ther. Targets 21, 751–753), elucidating the atomic resolution structure of LRRK2 has been a major goal of research into this protein. At over 250 kDa, the large size and complicated domain organisation of LRRK2 has made this a highly challenging target for structural biologists, however, a number of recent studies using both in vitro and in situ approaches (Nature 588, 344–349; Cell 182, 1508–1518.e1516; Cell 184, 3519–3527.e3510) have provided important new insights into LRRK2 structure and the complexes formed by this protein.

scholarly journals Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice

2020 ◽  
Author(s):  
Francois Singh ◽  
Alan R. Prescott ◽  
Graeme Ball ◽  
Alastair D. Reith ◽  
Ian G. Ganley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Neurodegenerative Disorder ◽  
Reporter Mice ◽  
Lrrk2 G2019s ◽  
Lrrk2 Kinase

AbstractParkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of the autophagy of mitochondria, known as mitophagy. Here we investigated the role of LRRK2, a protein kinase frequently mutated in PD, on this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson’s disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.

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 Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients

2019 ◽  
Vol 476 (19) ◽  
pp. 2797-2813 ◽  
Author(s):  
Belén Fernández ◽  
Antonio Jesús Lara Ordóñez ◽  
Elena Fdez ◽  
Eugénie Mutez ◽  
Thomas Comptdaer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Lymphoblastoid Cell Lines ◽  
Peripheral Blood Mononuclear ◽  
Kinase Substrate ◽  
Promising Therapeutic Target ◽  
Lrrk2 Kinase ◽  
Orally Bioavailable

Abstract Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD), and orally bioavailable, brain penetrant and highly potent LRRK2 kinase inhibitors are in early stages of clinical testing. Detection of LRRK2 phosphorylation, as well as phosphorylation of Rab10, a LRRK2 kinase substrate, have been proposed as target engagement biomarkers for LRRK2 inhibitor clinical trials. However, these readouts do not seem able to stratify patients based on enhanced LRRK2 kinase activity. Here, we describe a robust cell biological assay based on centrosomal cohesion alterations which were observed in peripheral blood mononuclear cell-derived lymphoblastoid cell lines (LCLs) from patients with G2019S LRRK2 mutations as compared with healthy controls, and could also be detected in a subset of sporadic PD patient samples. We suggest that LCLs may be a valuable resource for LRRK2 research, and that determination of centrosomal cohesion deficits may assist in the stratification of a subset of sporadic PD patients.

scholarly journals Parkinson’s Disease-linked LRRK2 structure and model for microtubule interaction

2020 ◽  
Author(s):  
Colin K. Deniston ◽  
John Salogiannis ◽  
Sebastian Mathea ◽  
David M. Snead ◽  
Indarjit Lahiri ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Membrane Trafficking ◽  
Kinase Inhibitors ◽  
Electron Tomography ◽  
Kinase Domain ◽  
Closed Conformation ◽  
Lrrk2 Kinase

AbstractLeucine Rich Repeat Kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson’s disease. LRRK2 is proposed to function in membrane trafficking and co-localizes with microtubules. We report the 3.5Å structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported 14Å cryo-electron tomography in situ structure. We propose that the conformation of LRRK2’s kinase domain regulates its microtubule interaction, with a closed conformation favoring binding. We show that the catalytic half of LRRK2 is sufficient for microtubule binding and blocks the motility of the microtubule-based motors kinesin and dynein in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce LRRK2 filament formation in cells, while those that stabilize a closed conformation do not. Our findings suggest that LRRK2 is a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.

scholarly journals Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Martin Steger ◽  
Francesca Tonelli ◽  
Genta Ito ◽  
Paul Davies ◽  
Matthias Trost ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitors ◽  
Rab Gtpases ◽  
Common Amino Acid ◽  
Bona Fide ◽  
Lrrk2 Kinase ◽  
Conserved Residue

Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD.

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.

scholarly journals LRRK2 kinase inhibitors induce a reversible effect in the lungs of non-human primates with no measurable pulmonary deficits

2018 ◽  
Author(s):  
Marco A.S. Baptista ◽  
Kalpana Merchant ◽  
Ted Barrett ◽  
Diane K. Bryce ◽  
Michael Ellis ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Low Dose ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Clinical Investigation ◽  
Positive Control ◽  
Histopathological Changes ◽  
Lrrk2 Kinase ◽  
Target Effect

AbstractPutative gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2), resulting in increased kinase activity and cellular toxicity, are a leading genetic cause of Parkinson’s disease (PD). Hence, there is strong interest in developing LRRK2 kinase inhibitors as a disease-modifying therapy. Published reports that repeat dosing with two LRRK2 kinase inhibitors (GNE-7915 and GNE-0877) induce histopathological changes in the lung of non-human primates Fuji et al. 2015 (1) raised concerns about potential safety liability of LRRK2 kinase inhibitors. In the present study, we sought to determine whether previously observed effects in the lung: (a) represent on-target pharmacology, but with the potential for margin of safety, (b) are reversible upon drug withdrawal, and (c) are associated with pulmonary function deficits. To this end, we evaluated the histopathological effects, toxicokinetics and target inhibition of three structurally diverse LRRK2 kinase inhibitors, GNE-7915 (30 mg/kg, BID, as a positive control), MLi-2 (15 and 50 mg/kg, QD) and PFE-360 (3 and 6 mg/kg, QD) following 2 weeks of dosing in non-human primates. Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated after 2-week dose-free periods. All three LRRK2 kinase inhibitors induced mild cytoplasmic vacuolation of type II pneumocytes, as reported previously, confirming an on-target effect of these compounds. Interestingly, despite lower doses of both PFE-360 and MLi-2 producing nearly complete inhibition of LRRK2 kinase activity in the brain as assessed by levels of pS935-LRRK2, histopathological changes in lung were absent in animals treated with low-dose PFE-360 and observed only sporadically in the low-dose MLi-2 group. The lung effect was fully reversible at 2 weeks post-dosing of GNE-7915. In a second study of identical dosing with MLi-2 and GNE-7915, no deficits were observed in a battery of translational pulmonary functional tests. In aggregate, these results do not preclude the development of LRRK2 kinase inhibitors for clinical investigation in Parkinson’s disease.

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