ArticleBiochimica et biophysica acta2014
Mutant LRRK2 enhances glutamatergic synapse activity and evokes excitotoxic dendrite degeneration.
Article in Biochimica et biophysica acta, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- Generation of Leucine-Rich Repeat Kinase 2 (LRRK2) Knockout Neuroblastoma Cells SH-SY5Y by CRISPR/Cas9-Mediated Genome Editing.Biochemical genetics · 2026Article
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.Autophagy reports · 2025Article
- Impairment of the trans-Golgi-Lysosomal Pathway Accelerates Dopaminergic Neuronal Senescence in LRRK2Aging and disease · 2024Article
- Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.Aging and disease · 2024Review
- Knocking out the LRRK2 gene increases sensitivity to wavelength information in rats.Scientific reports · 2024Article
- Autophagy and autophagy-related molecules in neurodegenerative diseases.Animal models and experimental medicine · 2023Review
- The Role of Rab Proteins in Parkinson's Disease Synaptopathy.Biomedicines · 2022Review
- Mitochondria in neurodegeneration.Current opinion in physiology · 2022Article
- Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration.Translational neurodegeneration · 2022Review
- Review
- Validation of the functions and prognostic values of synapse-associated proteins in lower-grade glioma.Bioscience reports · 2021Article
- Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson's Disease.Frontiers in cellular neuroscience · 2021Article
- G2019S-LRRK2 mutation enhances MPTP-linked Parkinsonism in mice.Human molecular genetics · 2020Article
- Dysregulated Plasma Membrane Turnover Underlying Dendritic Pathology in Neurodegenerative Diseases.Frontiers in cellular neuroscience · 2020Review
- Sleep Spindles and Fragmented Sleep as Prodromal Markers in a Preclinical Model of LRRK2-G2019S Parkinson's Disease.Frontiers in neurology · 2020Article
- Sensory neuropathy and nociception in rodent models of Parkinson's disease.Disease models & mechanisms · 2019Review
- Crosstalk between presynaptic trafficking and autophagy in Parkinson's disease.Neurobiology of disease · 2019Review
- Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases.Neurobiology of disease · 2019Review
- LRRK2 G2019S Induces Anxiety/Depression-like Behavior before the Onset of Motor Dysfunction with 5-HTThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2), which are associated with autosomal dominant Parkinson's disease, elicit progressive dendrite degeneration in neurons. We hypothesized that synaptic dysregulation contributes to mutant LRRK2-induced dendritic injury. We performed in vitro whole-cell voltage clamp studies of glutamatergic receptor agonist responses and glutamatergic synaptic activity in cultured rat cortical neurons expressing full-length wild-type and mutant forms of LRRK2. Expression of the pathogenic G2019S or R1441C LRRK2 mutants resulted in larger whole-cell current responses to direct application of AMPA and NMDA receptor agonists. In addition, mutant LRRK2-expressing neurons exhibited an increased frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in conjunction with increased excitatory synapse density as assessed by immunofluorescence for PSD95 and VGLUT1. Mutant LRRK2-expressing neurons showed enhanced vulnerability to acute synaptic glutamate stress. Furthermore, treatment with the NMDA receptor antagonist memantine significantly protected against subsequent losses in dendrite length and branching complexity. These data demonstrate an early association between mutant LRRK2 and increased excitatory synapse activity, implicating an excitotoxic contribution to mutant LRRK2 induced dendrite degeneration.
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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.