ArticleHuman molecular genetics2014
Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers.
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Who cites it
131 citing papers in PubMed, 224 citations in OpenAlex.
- Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.International journal of molecular sciences · 2026Review
- Parkinson's disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes.Molecular neurodegeneration · 2026Article
- Generation of Leucine-Rich Repeat Kinase 2 (LRRK2) Knockout Neuroblastoma Cells SH-SY5Y by CRISPR/Cas9-Mediated Genome Editing.Biochemical genetics · 2026Article
- Prenatal diisononyl phthalate exposure induces the development of pulmonary dysplasia in offspring.Scientific reports · 2026Article
- Wdfy3-dependent autophagy impairment recapitulates presymptomatic neurodegenerative signatures in mice.Scientific reports · 2026Article
- LRRK2 G2019S reprograms innate and adaptive immunity to drive context-dependent host defense outcomes.Frontiers in cellular neuroscience · 2026Article
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- The G2019S LRRK2 mutation exacerbates α-synuclein and tau neuropathology through divergent pathways in Parkinson's disease models.Acta neuropathologica · 2025Article
- Regulation of LRRK2 activity by metabolic stress and heavy metal exposure.Brain research · 2025Article
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- Longitudinal assessment of the association between pesticide exposure and lifestyle with Parkinson's disease motor severity.NPJ Parkinson's disease · 2025Article
- The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.Autophagy reports · 2025Article
- Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.eLife · 2024Article
- Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Review
- Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.Cellular and molecular life sciences : CMLS · 2024Review
- How Parkinson's Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types.Journal of Parkinson's disease · 2024Review
- Article
- Leucine-rich repeat kinase 2 promotes the development of experimental severe acute pancreatitis.Clinical and experimental immunology · 2023Article
- ASO-mediated knockdown or kinase inhibition ofMolecular therapy. Nucleic acids · 2023Article
- LRRK2 G2019S promotes astrocytic inflammation induced by oligomeric α-synuclein through NF-κB pathway.iScience · 2023Article
71 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and idiopathic Parkinson's disease. However, the mechanisms for activating its physiological function are not known, hindering identification of the biological role of endogenous LRRK2. The recent discovery that LRRK2 is highly expressed in cells of the innate immune system and genetic association is a risk factor for autoimmune disorders implies an important role for LRRK2 in pathology outside of the central nervous system. Thus, an examination of endogenous LRRK2 in immune cells could provide insight into the protein's function. Here, we establish that stimulation of specific Toll-like receptors results in a complex biochemical activation of endogenous LRRK2, with early phosphorylation of LRRK2 preceding its dimerization and membrane translocation. Membrane-associated LRRK2 co-localized to autophagosome membranes following either TLR4 stimulation or mTOR inhibition with rapamycin. Silencing of endogenous LRRK2 expression resulted in deficits in the induction of autophagy and clearance of a well-described macroautophagy substrate, demonstrating the critical role of endogenous LRRK2 in regulating autophagy. Inhibition of LRRK2 kinase activity also reduced autophagic degradation and suggested the importance of the kinase domain in the regulation of autophagy. Our results demonstrate a well-orchestrated series of biochemical events involved in the activation of LRRK2 important to its physiological function. With similarities observed across multiple cell types and stimuli, these findings are likely relevant in all cell types that natively express endogenous LRRK2, and provide insights into LRRK2 function and its role in human disease.
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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.