A5077137526- Parkinson's Disease Mechanisms and Treatments
- Neuroscience and Neuropharmacology Research
- Neurological disorders and treatments
- Genetics and Neurodevelopmental Disorders
- Amino Acid Enzymes and Metabolism
- Genomic variations and chromosomal abnormalities
- Receptor Mechanisms and Signaling
- Congenital heart defects research
- Botulinum Toxin and Related Neurological Disorders
- Drug Transport and Resistance Mechanisms
- Genetic Neurodegenerative Diseases
- Plant Gene Expression Analysis
- Pharmacological Effects and Toxicity Studies
- Fungal and yeast genetics research
- RNA regulation and disease
- Autism Spectrum Disorder Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Coffee research and impacts
- Epigenetics and DNA Methylation
- Muscle metabolism and nutrition
- Retinal Development and Disorders
- Exercise and Physiological Responses
- Nuclear Receptors and Signaling
- Alzheimer's disease research and treatments
- Adipose Tissue and Metabolism
Lundbeck (Denmark)
2011-2021
Servier (France)
2019-2020
Institut des Hautes Études Scientifiques
2020
Plateforme Technologique d'Innovation Biomédicale
2019
Drug Discovery Laboratory (Norway)
2018
Granta Design (United Kingdom)
2017
Lundbeck Foundation
2016
University of Copenhagen
2016
University of Cambridge
2016
Centro de Investigación Biomédica en Red de Salud Mental
2016
Abstract Genetic variation in the leucine-rich repeat kinase 2 ( LRRK2 ) gene is associated with risk of familial and sporadic Parkinson’s disease (PD). To support clinical development inhibitors as disease-modifying treatment PD biomarkers for activity, target engagement inhibition are prerequisite tools. In a combined proteomics phosphoproteomics study on human peripheral mononuclear blood cells (PBMCs) treated inhibitor Lu AF58786 number putative were identified. Among phospho-site hits...
<h3>Background:</h3> The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of carriers experience psychotic symptoms. <h3>Methods:</h3> We present new mouse model (Df(h22q11)/+) the syndrome (22q11.2DS) report on, our knowledge, most comprehensive study undertaken date 22q11.2DS models. was conducted male mice. <h3>Results:</h3> found elevated postpubertal...
d-Serine is a co-agonist of NMDA receptors (NMDARs) whose activity potentially regulated by Asc-1 (SLC7A10), transporter that displays high affinity for d-serine and glycine. operates as facilitative an antiporter, though the preferred direction transport uncertain. We developed selective blocker, Lu AE00527, blocks release mediated all modes in primary cultures neocortical slices. Furthermore, reduced slices from knockout (KO) mice, indicating efflux Asc-1. The selectivity AE00527 assured...
Parkinson’s disease (PD) is a progressive neurodegenerative disorder for which there no existing therapeutic approach to delay or stop progression. Genetic, biochemical and pre-clinical studies have provided evidence that leucine-rich-repeat-kinase-2 (LRRK2) kinase involved in the pathogenesis of PD, small molecule LRRK2 inhibitors represent novel potential approach. However, potentially adverse target-related effects been discovered lung kidneys knock-out (ko) mice rats. It unclear if ko...
Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 domain based on checkpoint 1 (CHK1) mutants were designed, expressed insect cells infected baculovirus, purified, and crystallized. X-ray structures surrogates complexed known inhibitors rationalized compound potency selectivity. The CHK1 10-point mutant was preferred, following assessment surrogate binding affinity inhibitors....
1q21.1 hemizygous microdeletion is a copy number variant leading to eightfold increased risk of schizophrenia. In order investigate biological alterations induced by this microdeletion, we generated novel mouse model (Df(h1q21)/+) and characterized it in broad test battery focusing on schizophrenia-related assays. Df(h1q21)/+ mice displayed hyperactivity response amphetamine challenge sensitivity the disruptive effects phencyclidine hydrochloride (PCP) prepulse inhibition. Probing direct...
The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. Hippocampal RNA isolated from rats at different kindling stages was analyzed to identify kindling-induced genes. Furthermore, effects of the anti-epileptic drug levetiracetam on gene expression were examined.Cyclooxygenase-2 (Cox-2), Protocadherin-8 (Pcdh8) TGF-beta-inducible early response gene-1 (TIEG1) identified verified as differentially expressed transcripts in hippocampus...
Our understanding of Parkinson's disease (PD) has been revolutionized by the discovery disease-causing genetic mutations. The most common these is G2019S mutation in LRRK2 kinase gene, which leads to increased activity. However, link between activity and PD unclear. Previously, we showed that dopaminergic expression human LRRK2-G2019S transgene flies led an activity-dependent loss vision older animals hypothesized this may have preceded a failure regulate neuronal correctly younger animals....
Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures LRRK2 domain surrogates, based on checkpoint 1 (CHK1) a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi 0.7 nM, LE 0.66) was identified, with increased potency consistent an structure 18/CHK1 10-pt. mutant showing the 2-methyl...
Abstract Background Preclinical evidence suggests that co‐administration of the 5‐HT 1A agonist buspirone and 1B/1D zolmitriptan act synergistically to reduce dyskinesia a greater extent than achieved by either drug alone. Objectives Assess therapeutic potential fixed‐dose combination in Parkinson's disease (PD) patients with levodopa‐induced dyskinesia. Methods Single‐center, randomized, placebo‐controlled, two‐way crossover study (NCT02439203) buspirone/zolmitriptan regimen (10/1.25 mg...
BACKGROUND AND PURPOSE Intestinal absorption via membrane transporters may determine the pharmacokinetics of drug compounds. The hypothesis is that oral gaboxadol (4,5,6,7‐tetrahydroisoxazolo [5,4‐c] pyridine‐3‐ol) in rats occurs proton‐coupled amino acid transporter, rPAT1 (encoded by gene rSlc36a1 ). Consequently, we aimed to elucidate vivo role from various intestinal segments obtained Sprague‐Dawley rats. EXPERIMENTAL APPROACH was investigated following its administration into four...
The purpose of this study was to investigate the influence an energy drink (ED) on cycling performance and immune-related variables. Eleven trained male cyclists (33.4 ± 8.9 years; 81 7.6 kg; maximal VO2, 52 3.4 ml·kg(-1)·min(-1)) consumed 500 ml (a) ED (2.0 g taurine, 1.2 glucuronolactone, 160 mg caffeine, 56 carbohydrate [CHO], B vitamins), (b) cola matched for caffeine CHO (CC), or (c) flavored placebo (PL: sparking water flavoring) 50 minutes before racing in a randomized, crossover...
Abstract Leucine-rich repeat kinase 2 (LRRK2) is associated to Parkinson’s disease (PD). The most common form of LRRK2 PD caused by the G2019S variant. Besides G2019S, eight other variants causing familial also have amino acid substitutions located in a enzymatic domainsuggesting that activity at core mechanisms underlying risk. Common polymorphic risk variations such as G2385R, A419V, R1628 and M1646T all reside domains. Prior knowledge limited on how these influence function. To...
The glucocorticoid receptor (GR) and myocyte enhancer factor 2 (MEF2) are transcription factors involved in neuronal plasticity. c-JUN, a target gene of GR MEF2, plays role regulating both synaptic strength synapse number. aim this study was to investigate the nature dual regulation c-JUN by MEF2 context. First, we showed that mediates dexamethasone-induced suppression mRNA expression. Next, observed activation resulted an increase phosphorylation post-translational modification known change...
Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences vulnerability for psychosis are reflected differential sensitivity psychostimulants such as amphetamine. We hypothesize that same genes and pathways underlying behavioral sensitization mice also involved to psychosis.The aim of current study was investigate which may contribute different output areas mouse brain.We took advantage naturally occurring difference...