Small Molecule Kinase Inhibitors for LRRK2 and Their Application to Parkinson's Disease Models

Krämer, Thomas; Monte, Fabio Lo; Göring, Stefan; Amombo, Ghislaine Marlyse Okala; Schmidt, Boris

doi:10.1021/cn200117j

Cited by 50 publications

(37 citation statements)

References 80 publications

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“…In line with our data, an in vivo study in LRRK2 mutant animals has suggested an involvement of LRRK2 in neurotransmitter release . Our data further suggest that this function of LRRK in flies is mediated by LRRK2 and not LRRK1 in the mammalian system, as LRRK2-IN-1 does not inhibit LRRK1 kinase function (Kramer et al, 2012). Future studies in LRRK1-knockout neurons could strengthen this hypothesis further.…”

Section: Discussionsupporting

confidence: 50%

LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

Arranz

Delbroek

Kolen

et al. 2014

Journal of Cell Science

142

136

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, but the precise physiological function of the protein remains ill-defined. Recently, our group proposed a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses in the Drosophila melanogaster neuromuscular junctions. Flies harbor only one Lrrk gene, which might encompass the functions of both mammalian LRRK1 and LRRK2. We therefore studied the role of LRRK2 in mammalian synaptic function and provide evidence that knockout or pharmacological inhibition of LRRK2 results in defects in synaptic vesicle endocytosis, altered synaptic morphology and impairments in neurotransmission. In addition, our data indicate that mammalian endophilin A1 (EndoA1, also known as SH3GL2) is phosphorylated by LRRK2 in vitro at T73 and S75, two residues in the BAR domain. Hence, our results indicate that LRRK2 kinase activity has an important role in the regulation of clathrin-mediated endocytosis of synaptic vesicles and subsequent neurotransmission at the synapse.

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Section: Discussionsupporting

confidence: 50%

LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

Arranz

Delbroek

Kolen

et al. 2014

Journal of Cell Science

142

136

View full text Add to dashboard Cite

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“…A large number of ATP competitive type I inhibitors of LRRK2 have been reported from screening studies and recently reviewed (21, 86, 87). In addition, homology models of LRRK2 built by other research groups have been used successfully to drive SAR studies for ATP-competitive inhibitors (88).…”

Section: Discussionmentioning

confidence: 99%

Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S

et al. 2013

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A number of well-known type II inhibitors (ATP non-competitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work by an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected non-competitive mechanism against WT. Since the G2019S mutation lies in the DXG-motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the conformational barrier between the active and inactive forms of the enzyme and a relative stabilization of the active form. The conformational bias toward the active form of LRRK2 mutants has two primary consequences: 1) the mutant enzyme becomes hyperactive, a known contributor to the Parkinsonian phenotype, as a consequence of being “locked” into the activated state and 2) the mutation creates an unusual allosteric pocket that can bind type II inhibitors but in an ATP competitive fashion. Our results suggest that developing type II inhibitors, which are generally considered superior to type I inhibitors due to desirable selectivity profiles, might be especially challenging for the G2019S LRRK2 mutant.

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“…As the most common LRRK2 mutation (G2019S) augments kinase activity, development of LRRK2 kinase inhibitors has been proposed as a promising approach [156]. Many kinase inhibitors will block LRRK2 activity, with CZC-25146 and LRRK2-IN1 having high specificity for LRRK2 [157][158][159]. Neither of these kinase inhibitors would be taken into clinical trials owing to their poor blood-brain barrier permeability [159], although more recent inhibitors may be have better distribution in the brain [160][161][162].…”

Section: Therapeutic Strategies For Lrrk2-associated Pdmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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Small Molecule Kinase Inhibitors for LRRK2 and Their Application to Parkinson's Disease Models

Cited by 50 publications

References 80 publications

LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

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