gsk2578215a and Parkinson-Disease

Mutations in LRRK2 comprise the most common cause for familial Parkinson's disease (PD), and variations increase risk for sporadic disease, implicating LRRK2 in the entire disease spectrum. LRRK2 is a large protein harbouring both GTPase and kinase domains which display measurable catalytic activity. Most pathogenic mutations increase the kinase activity, with increased activity being cytotoxic under certain conditions. These findings have spurred great interest in drug development approaches, and various specific LRRK2 kinase inhibitors have been developed. However, LRRK2 is a largely ubiquitously expressed protein, and inhibiting its function in some non-neuronal tissues has raised safety liability issues for kinase inhibitor approaches. Therefore, understanding the cellular and cell type-specific role(s) of LRRK2 has become of paramount importance. This review will highlight current knowledge on the precise biochemical activities of normal and pathogenic LRRK2, and highlight the most common proposed cellular roles so as to gain a better understanding of the cell type-specific effects of LRRK2 modulators.

Topics: alpha-Synuclein; Aminopyridines; Antiparkinson Agents; Autophagy; Benzamides; Endocytosis; Gene Expression; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Neurons; Parkinson Disease; Protein Domains; Protein Kinase Inhibitors; rab GTP-Binding Proteins; rab1 GTP-Binding Proteins; rab7 GTP-Binding Proteins

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent cause of familial and sporadic Parkinson's disease (PD). Because most pathogenic LRRK2 mutations result in enhanced kinase activity, it suggests that LRRK2 inhibitors may serve as a potential treatment for PD. To evaluate whether LRRK2 inhibitors are effective therapies for PD, it is crucial to know whether LRRK2 inhibitors will affect dopaminergic (DAergic) neurotransmission. However, to date, there is no study to investigate the impact of LRRK2 inhibitors on DAergic neurotransmission.. To address this gap in knowledge, we examined the effects of three types of LRRK2 inhibitors (LRRK2-IN-1, GSK2578215A, and GNE-7915) on dopamine (DA) release in the dorsal striatum using fast-scan cyclic voltammetry and DA neuron firing in the substantia nigra pars compacta (SNpc) using patch clamp in mouse brain slices.. We found that LRRK2-IN-1 at a concentration higher than 1 μM causes off-target effects and decreases DA release, whereas GSK2578215A and GNE-7915 do not. All three inhibitors at 1 μM have no effect on DA release and DA neuron firing rate. We have further assessed the effects of the inhibitors in two preclinical LRRK2 mouse models (i.e., BAC transgenic hG2019S and hR1441G) and demonstrated that GNE-7915 enhances DA release and synaptic vesicle mobilization/recycling.. GNE-7915 can be validated for further therapeutic development for PD.

Topics: Aminopyridines; Animals; Benzamides; Benzodiazepinones; Biophysical Phenomena; Corpus Striatum; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Electric Stimulation; In Vitro Techniques; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Mice; Mice, Transgenic; Morpholines; Mutation; Parkinson Disease; Patch-Clamp Techniques; Pyrimidines; Substantia Nigra

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for some forms of Parkinson's disease. Here we report the discovery and characterization of 2-arylmethyloxy-5-subtitutent-N-arylbenzamides with potent LRRK2 activities exemplified by GSK2578215A which exhibits biochemical IC(50)s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. GSK2578215A exhibits exceptionally high selectivity for LRRK2 across the kinome, substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.3-1.0 μM in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100mg/kg.

Topics: 3T3 Cells; Animals; Brain; Cell Line; Drug Discovery; HEK293 Cells; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Mice; Models, Molecular; Mutation; Parkinson Disease; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Structural Homology, Protein