ArticleJournal of neuroinflammation2016
Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons.
Article in Journal of neuroinflammation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 58 citations in OpenAlex.
- The LRRK2 P1446L mutation triggers dopaminergic neurodegeneration via DAPK1-mediated microglial neuroinflammation and neuronal apoptosis.NPJ Parkinson's disease · 2025Article
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- The Multifaceted Role of LRRK2 in Parkinson's Disease.Brain sciences · 2025Review
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- Comparative Analysis of Different Extracellular Matrices for the Maintenance of Bovine Satellite Cells.Animals : an open access journal from MDPI · 2024Article
- Mitophagy related diagnostic biomarkers for coronary in-stent restenosis identified using machine learning and bioinformatics.Scientific reports · 2024Article
- The Neuroanatomy of Induced Pluripotent Stem Cells: In Vitro Models of Subcortical Nuclei in Neurodegenerative Disorders.Current issues in molecular biology · 2024Review
- The link between neuroinflammation and the neurovascular unit in synucleinopathies.Science advances · 2023Review
- Human Induced Pluripotent Stem Cell Phenotyping and Preclinical Modeling of Familial Parkinson's Disease.Genes · 2022Review
- The parkinsonian LRRK2 R1441G mutation shows macroautophagy-mitophagy dysregulation concomitant with endoplasmic reticulum stress.Cell biology and toxicology · 2022Article
- In Vitro Methodologies to Study the Role of Advanced Glycation End Products (AGEs) in Neurodegeneration.Nutrients · 2022Review
- Review
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- Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases.Biology · 2021Review
- Review
- Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases.Frontiers in neuroscience · 2021Review
- Interferon-γ signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem cells.Nature communications · 2020Article
- Review
- Organoid and pluripotent stem cells in Parkinson's disease modeling: an expert view on their value to drug discovery.Expert opinion on drug discovery · 2020Review
- Using induced pluripotent stem cell neuronal models to study neurodegenerative diseases.Biochimica et biophysica acta. Molecular basis of disease · 2020Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both familial and idiopathic forms of Parkinson's disease (PD). Neuroinflammation is a key event in neurodegeneration and aging, and there is mounting evidence of LRRK2 involvement in inflammatory pathways. In a previous study, we described an alteration of the inflammatory response in dermal fibroblasts from PD patients expressing the G2019S and R1441G mutations in LRRK2.
methodsTaking advantage of cellular reprogramming, we generated induced pluripotent stem cell (iPSC) lines and neurons thereafter, harboring LRRK2
resultsLRRK2 silencing decreased α-synuclein protein levels in mutated neurons and modified NF-κB transcriptional targets, such as PTGS2 (COX-2) and TNFAIP3 (A20). We next tested whether NF-κB and α-synuclein pathways converged and found that TNFα modulated α-synuclein levels, although we could not detect an effect of LRRK2 mutations, partly because of the individual variability. Nevertheless, we confirmed NF-κB dysregulation in mutated neurons, as shown by a protracted recovery of IκBα and a clear impairment in p65 nuclear translocation in the LRRK2 mutants.
conclusionsAltogether, our results show that LRRK2 mutations affect α-synuclein regulation and impair NF-κB canonical signaling in iPSC-derived neurons. TNFα modulated α-synuclein proteostasis but was not modified by the LRRK2 mutations in this paradigm. These results strengthen the link between LRRK2 and the innate immunity system underscoring the involvement of inflammatory pathways in the neurodegenerative process in PD.
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