ArticleHuman molecular genetics2015
Selective expression of Parkinson's disease-related Leucine-rich repeat kinase 2 G2019S missense mutation in midbrain dopaminergic neurons impairs dopamine release and dopaminergic gene expression.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 58 citations in OpenAlex.
- Strategies for Optimizing Genetic Mouse Models to Enhance the Understanding of Parkinson's Disease.Biomedicines · 2026Review
- Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson's disease.The Journal of cell biology · 2025Article
- Article
- Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2bioRxiv : the preprint server for biology · 2024Article
- Cell-autonomous role of leucine-rich repeat kinase in the protection of dopaminergic neuron survival.eLife · 2024Article
- Molecular dynamic investigation for Roco4 kinase inhibitor as treatment options for parkinsonism.Journal of molecular modeling · 2024Article
- Modeling Parkinson's disease in LRRK2 rodents.Neuronal signaling · 2023Review
- Impaired dopamine release in Parkinson's disease.Brain : a journal of neurology · 2023Review
- Deficiency of Perry syndrome-associated p150NPJ Parkinson's disease · 2023Article
- Dopamine Transporter, PhosphoSerine129 α-Synuclein and α-Synuclein Levels in Aged LRRK2 G2019S Knock-In and Knock-Out Mice.Biomedicines · 2022Article
- Age-related LRRK2 G2019S Mutation Impacts Microglial Dopaminergic Fiber Refinement and Synaptic Pruning Involved in Abnormal Behaviors.Journal of molecular neuroscience : MN · 2022Article
- LRRK2 mutant knock-in mouse models: therapeutic relevance in Parkinson's disease.Translational neurodegeneration · 2022Review
- Selective expression of neurodegenerative diseases-related mutant p150Ageing and neurodegenerative diseases · 2022Article
- Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson's disease.NPJ Parkinson's disease · 2020Article
- Lrrk2 modulation of Wnt signaling during zebrafish development.Journal of neuroscience research · 2020Article
- G2019S-LRRK2 mutation enhances MPTP-linked Parkinsonism in mice.Human molecular genetics · 2020Article
- From Synaptic Dysfunction to Neuroprotective Strategies in Genetic Parkinson's Disease: Lessons From LRRK2.Frontiers in cellular neuroscience · 2020Review
- A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2.Frontiers in molecular neuroscience · 2020Review
- LRRK2 and Protein Aggregation in Parkinson's Disease: Insights From Animal Models.Frontiers in neuroscience · 2020Review
- Progress inFrontiers in neuroscience · 2020Review
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Authors and funding
15 authors at 6 institutions in 2 countries.
Funding
Abstract
Preferential dysfunction/degeneration of midbrain substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons contributes to the main movement symptoms manifested in Parkinson's disease (PD). Although the Leucine-rich repeat kinase 2 (LRRK2) G2019S missense mutation (LRRK2 G2019S) is the most common causative genetic factor linked to PD, the effects of LRRK2 G2019S on the function and survival of SNpc DA neurons are poorly understood. Using a binary gene expression system, we generated transgenic mice expressing either wild-type human LRRK2 (WT mice) or the LRRK2 G2019S mutation (G2019S mice) selectively in the midbrain DA neurons. Here we show that overexpression of LRRK2 G2019S did not induce overt motor abnormalities or substantial SNpc DA neuron loss. However, the LRRK2 G2019S mutation impaired dopamine homeostasis and release in aged mice. This reduction in dopamine content/release coincided with the degeneration of DA axon terminals and decreased expression of DA neuron-enriched genes tyrosine hydroxylase (TH), vesicular monoamine transporter 2, dopamine transporter and aldehyde dehydrogenase 1. These factors are responsible for dopamine synthesis, transport and degradation, and their expression is regulated by transcription factor paired-like homeodomain 3 (PITX3). Levels of Pitx3 mRNA and protein were similarly decreased in the SNpc DA neurons of aged G2019S mice. Together, these findings suggest that PITX3-dependent transcription regulation could be one of the many potential mechanisms by which LRRK2 G2019S acts in SNpc DA neurons, resulting in downregulation of its downstream target genes critical for dopamine homeostasis and release.
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