ArticleJournal of molecular neuroscience : MN2022
Age-related LRRK2 G2019S Mutation Impacts Microglial Dopaminergic Fiber Refinement and Synaptic Pruning Involved in Abnormal Behaviors.
Article in Journal of molecular neuroscience : MN, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 21 citations in OpenAlex.
- Retromer-targeted therapy for neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- Strategies for Optimizing Genetic Mouse Models to Enhance the Understanding of Parkinson's Disease.Biomedicines · 2026Review
- LRRK2 deficiency mitigates amyloid β deposition-mediated pathology in a murine Alzheimer's disease model by reprogramming microglia.Translational psychiatry · 2025Article
- Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson's disease.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice.Journal of neuroinflammation · 2024Article
- How Parkinson's Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types.Journal of Parkinson's disease · 2024Review
- LRRK2; Communicative Role in the Treatment of Parkinson's Disease and Ulcerative Colitis Overlapping.CNS & neurological disorders drug targets · 2024Review
- Microglia: roles and genetic risk in Parkinson's disease.Frontiers in neuroscience · 2024Review
- Caffeine intake interacts with Asian gene variants in Parkinson's disease: a study in 4488 subjects.The Lancet regional health. Western Pacific · 2023Article
- LRRK2 Deficiency Aggravates Sleep Deprivation-Induced Cognitive Loss by Perturbing Synaptic Pruning in Mice.Brain sciences · 2022Article
- Age-Dependent Neuropsychiatric Symptoms in the NF-κB/c-Rel Knockout Mouse Model of Parkinson's Disease.Frontiers in behavioral neuroscience · 2022Article
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Authors and funding
9 authors at 1 institution in 1 country.
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Abstract
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of autosomal dominant Parkinson's disease (PD), producing psychiatric and motor symptoms. We conducted this study to explore whether microglial dopaminergic (DAergic) fiber refinement and synaptic pruning are involved in the abnormal behavioral phenotypes of carriers of the LRRK2 G2019S mutation, by employing young and middle-aged PD model mice. The results revealed a characteristic late-onset hyperactivity and a progressive decline in the motor coordination of the LRRK2 G2019S mutation mice. LRRK2 G2019S mutation-induced aberrant microglial morphogenesis, with more branches and junctions per cell, resulted in excessive microglial refinement of dopaminergic (DAergic) fibers. Moreover, aberrant synaptic pruning distinctly impacted the prefrontal cortex (PFC) and dorsal striatum (DS), with significantly higher spine density in the PFC but the opposite effects in the DS region. Furthermore, LRRK2 G2019S mutation remodeled the inflammatory transcription landscape of microglia, rendering certain cerebral areas highly susceptible to microglial immune response. These findings indicate that LRRK2 G2019S mutation induces the production of inflammatory cytokines and mediates abnormal microglial morphogenesis and activity, resulting in abnormal phagocytosis, synaptic pruning and loss of DAergic fibers during aging, and, eventually, PD-related behavioral abnormalities.
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