ArticleNeurobiology of disease2014
Genetic and pharmacological evidence that G2019S LRRK2 confers a hyperkinetic phenotype, resistant to motor decline associated with aging.
Article in Neurobiology of disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 57 citations in OpenAlex.
- Neuroinflammatory and Motor Alterations in LRRK2*G2019S Transgenic Mice Without Enhanced Vulnerability to Aging or Chronic MPTP-Induced Nigrostriatal Neurodegeneration.Journal of neurochemistry · 2026Article
- The Parkinson's disease-linked G2019S mutation of LRRK2 increases NADPH oxidase-2 activity in neutrophils for superior control of bacterial infections.Cellular & molecular immunology · 2026Article
- Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and ADHD.The Journal of clinical investigation · 2026Article
- Viral mediated α-synuclein overexpression results in greater transgene levels and α-synuclein overload in mice bearing kinase dead mutation of LRRK2.Scientific reports · 2025Article
- Advances in autophagy for Parkinson's disease pathogenesis and treatment.Ageing and neurodegenerative diseases · 2025Article
- Parkinson's LRRK2-G2019S risk gene mutation drives sex-specific behavioral and cellular adaptations to chronic variable stress.Frontiers in behavioral neuroscience · 2024Article
- Modeling Parkinson's disease in LRRK2 rodents.Neuronal signaling · 2023Review
- Cell-type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behavior in fragile X syndrome model mice.Cell reports · 2023Article
- Age- and Sex-Dependent Behavioral and Neurochemical Alterations in hLRRK2-G2019S BAC Mice.Biomolecules · 2022Article
- Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson's disease.Acta neuropathologica · 2022Article
- Dopamine Transporter, PhosphoSerine129 α-Synuclein and α-Synuclein Levels in Aged LRRK2 G2019S Knock-In and Knock-Out Mice.Biomedicines · 2022Article
- LRRK2-G2019S mice display alterations in glutamatergic synaptic transmission in midbrain dopamine neurons.Journal of neurochemistry · 2022Article
- LRRK2 mutant knock-in mouse models: therapeutic relevance in Parkinson's disease.Translational neurodegeneration · 2022Review
- Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function.Molecular psychiatry · 2021Article
- Deletion of lrrk2 causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain.PLoS genetics · 2021Article
- Review
- Sleep Spindles and Fragmented Sleep as Prodromal Markers in a Preclinical Model of LRRK2-G2019S Parkinson's Disease.Frontiers in neurology · 2020Article
- An Assessment of LRRK2 Serine 935 Phosphorylation in Human Peripheral Blood Mononuclear Cells in Idiopathic Parkinson's Disease and G2019S LRRK2 Cohorts.Journal of Parkinson's disease · 2020Article
- Origins of Parkinson's Disease in Brain Development: Insights From Early and Persistent Effects of LRRK2-G2019S on Striatal Circuits.Frontiers in neuroscience · 2020Review
- Progress inFrontiers in neuroscience · 2020Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
The leucine-rich repeat kinase 2 mutation G2019S in the kinase-domain is the most common genetic cause of Parkinson's disease. To investigate the impact of the G2019S mutation on motor activity in vivo, a longitudinal phenotyping approach was developed in knock-in (KI) mice bearing this kinase-enhancing mutation. Two cohorts of G2019S KI mice and wild-type littermates (WT) were subjected to behavioral tests, specific for akinesia, bradykinesia and overall gait ability, at different ages (3, 6, 10, 15 and 19months). The motor performance of G2019S KI mice remained stable up to the age of 19months and did not show the typical age-related decline in immobility time and stepping activity of WT. Several lines of evidence suggest that enhanced LRRK2 kinase activity is the main contributor to the observed hyperkinetic phenotype of G2019S KI mice: i) KI mice carrying a LRRK2 kinase-dead mutation (D1994S KD) showed a similar progressive motor decline as WT; ii) two LRRK2 kinase inhibitors, H-1152 and Nov-LRRK2-11, acutely reversed the hyperkinetic phenotype of G2019S KI mice, while being ineffective in WT or D1994S KD animals. LRRK2 target engagement in vivo was further substantiated by reduction of LRRK2 phosphorylation at Ser935 in the striatum and cortex at efficacious doses of Nov-LRRK2-11, and in the striatum at efficacious doses of H-1152. In summary, expression of the G2019S mutation in the mouse LRRK2 gene confers a hyperkinetic phenotype that is resistant to age-related motor decline, likely via enhancement of LRRK2 kinase activity. This study provides an in vivo model to investigate the effects of LRRK2 inhibitors on motor function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.