ArticleJournal of neuroinflammation2018
Leucine-rich repeat kinase 2 controls protein kinase A activation state through phosphodiesterase 4.
Article in Journal of neuroinflammation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- LRRK2 as a Potential Disease-Modifying Target in Sporadic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- The LRRK2 P1446L mutation triggers dopaminergic neurodegeneration via DAPK1-mediated microglial neuroinflammation and neuronal apoptosis.NPJ Parkinson's disease · 2025Article
- Striatal cell-type-specific molecular signatures reveal potential therapeutic targets in a model of dystonia.Neurobiology of disease · 2025Article
- Astrocytes carrying LRRK2 G2019S exhibit increased levels of clusterin chaperone via miR-22-5p and reduced ability to take up α-synuclein fibrils.Acta neuropathologica communications · 2025Article
- LRRK2 in Drosophila Melanogaster Model: Insights into Cellular Dysfunction and Neuroinflammation in Parkinson's Disease.International journal of molecular sciences · 2025Review
- Astrocytic and microglial cell functions in neuroinflammatory diseases and their animal models.Frontiers in cellular neuroscience · 2025Review
- Evaluation of Neuroinflammatory Contribution to Neurodegeneration in LRRK2Biomedicines · 2024Article
- Parkinson's-linked LRRK2-G2019S derails AMPAR trafficking, mobility, and composition in striatum with cell-type and subunit specificity.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Microglia: roles and genetic risk in Parkinson's disease.Frontiers in neuroscience · 2024Review
- Phosphodiesterase-4 Inhibition in Parkinson's Disease: Molecular Insights and Therapeutic Potential.Cellular and molecular neurobiology · 2023Review
- Article
- LRRK2 Kinase Inhibition Attenuates Astrocytic Activation in Response to Amyloid βBiomolecules · 2023Article
- Immunological Features of LRRK2 Function and Its Role in the Gut-Brain Axis Governing Parkinson's Disease.Journal of Parkinson's disease · 2023Review
- Human Induced Pluripotent Stem Cell Phenotyping and Preclinical Modeling of Familial Parkinson's Disease.Genes · 2022Review
- Review
- Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).International journal of molecular sciences · 2021Review
- The Emerging Role of Phosphodiesterases in Movement Disorders.Movement disorders : official journal of the Movement Disorder Society · 2021Review
- Article
- PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity.Theranostics · 2021Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundEvidence indicates a cross-regulation between two kinases, leucine-rich repeat kinase 2 (LRRK2) and protein kinase A (PKA). In neurons, LRRK2 negatively regulates PKA activity in spiny projecting neurons during synaptogenesis and in response to dopamine D1 receptor activation acting as an A-anchoring kinase protein (AKAP). In microglia cells, we showed that LRRK2 kinase activity negatively regulates PKA, impacting NF-κB p50 signaling and the inflammatory response. Here, we explore the molecular mechanism underlying the functional interaction between LRRK2 and PKA in microglia.
methodsTo understand which step of PKA signaling is modulated by LRRK2, we used a combination of in vitro and ex vivo systems with hyperactive or inactive LRRK2 as well as different readouts of PKA signaling.
resultsWe confirmed that LRRK2 kinase activity acts as a negative regulator of PKA activation state in microglia. Specifically, we found that LRRK2 controls PKA by affecting phosphodiesterase 4 (PDE4) activity, modulating cAMP degradation, content, and its dependent signaling. Moreover, we showed that LRRK2 carrying the G2019S pathological mutation downregulates PKA activation causing a reduction of PKA-mediated NF-κB inhibitory signaling, which results, in turn, in increased inflammation in LRRK2 G2019S primary microglia upon α-synuclein pre-formed fibrils priming.
conclusionsOverall, our findings indicate that LRRK2 kinase activity is a key regulator of PKA signaling and suggest PDE4 as a putative LRRK2 effector in microglia. In addition, our observations suggest that LRRK2 G2019S may favor the transition of microglia toward an overactive state, which could widely contribute to the progression of the pathology in LRRK2-related PD.
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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.