ArticleActa neuropathologica2022
Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson's disease.
Article in Acta neuropathologica, 2022. 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, 49 citations in OpenAlex.
- Astrocytes in Neurodegeneration: Spatial States, Crosstalk, and Emerging Therapies.Molecular neurobiology · 2026Review
- Protocol to quantify LRRK2-mediated Rab10 phosphorylation using high-content imaging.STAR protocols · 2026Article
- Written in the Stars: Astrocyte Biology From Evolution to Disease.Acta physiologica (Oxford, England) · 2026Review
- From Xenobiotic Exposure to Neuroinflammation: Mechanisms Linking Lipopolysaccharide Signaling to Depressive-like Behavior.Journal of xenobiotics · 2026Review
- Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway.Neuroscience bulletin · 2026Review
- Strategies for Optimizing Genetic Mouse Models to Enhance the Understanding of Parkinson's Disease.Biomedicines · 2026Review
- Reblastatin as a neuroprotective agent in temporal lobe epilepsy and excitotoxic conditions of Alzheimer's disease and Parkinson's disease.Acta pharmaceutica Sinica. B · 2026Article
- LRRK2 I1371V Mutation Drives Astrocytic Glucose Metabolism Failure and Induces Integrated ER-Mitochondria-Lysosome Dysfunction in Parkinson's Disease.International journal of molecular sciences · 2026Article
- Vacuolar protein sorting 35 regulates retinal neurovascular functionInternational journal of ophthalmology · 2026Article
- Molecular mechanisms of excitotoxicity and their relevance to the pathogenesis of neurodegenerative diseases-an update.Acta pharmacologica Sinica · 2025Review
- Short-Chain Fatty Acids Enhance EAAT2-Mediated Glutamate Clearance and Alleviate Oxidative Stress in an MPTP Mouse Model of Parkinson's Disease.Antioxidants (Basel, Switzerland) · 2025Article
- Alterations in the NaCerebellum (London, England) · 2025Article
- Role of dopaminergic RE1-silencing transcription factor (REST) in manganese-induced behavioral deficits and dysregulating dopaminergic and serotonergic neurotransmission in mice.Neurotoxicology · 2025Article
- Remote Regulation of Molecular Diffusion in Extracellular Space of Parkinson's Disease Rat Model by Subthalamic Nucleus Deep Brain Stimulation.Cyborg and bionic systems (Washington, D.C.) · 2025Article
- The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2).Journal of neurochemistry · 2025Article
- PAK6 rescues pathogenic LRRK2-mediated ciliogenesis and centrosomal cohesion defects in a mutation-specific manner.Cell death & disease · 2024Article
- The immune system in Parkinson's disease: what we know so far.Brain : a journal of neurology · 2024Review
- Five percent CONeuroprotection (Chichester, England) · 2024Article
- LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α.PLoS genetics · 2024Article
- Knocking out the LRRK2 gene increases sensitivity to wavelength information in rats.Scientific reports · 2024Article
Corrections and comments
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Authors and funding
21 authors at 9 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Excitatory Amino Acid Transporter 2 (EAAT2) accounts for 80% of brain glutamate clearance and is mainly expressed in astrocytic perisynaptic processes. EAAT2 function is finely regulated by endocytic events, recycling to the plasma membrane and degradation. Noteworthy, deficits in EAAT2 have been associated with neuronal excitotoxicity and neurodegeneration. In this study, we show that EAAT2 trafficking is impaired by the leucine-rich repeat kinase 2 (LRRK2) pathogenic variant G2019S, a common cause of late-onset familial Parkinson's disease (PD). In LRRK2 G2019S human brains and experimental animal models, EAAT2 protein levels are significantly decreased, which is associated with elevated gliosis. The decreased expression of the transporter correlates with its reduced functionality in mouse LRRK2 G2019S purified astrocytic terminals and in Xenopus laevis oocytes expressing human LRRK2 G2019S. In LRRK2 G2019S knock-in mouse brain, the correct surface localization of the endogenous transporter is impaired, resulting in its interaction with a plethora of endo-vesicular proteins. Mechanistically, we report that pathogenic LRRK2 kinase activity delays the recycling of the transporter to the plasma membrane via Rabs inactivation, causing its intracellular re-localization and degradation. Taken together, our results demonstrate that pathogenic LRRK2 interferes with the physiology of EAAT2, pointing to extracellular glutamate overload as a possible contributor to neurodegeneration in PD.
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