ArticleThe Journal of biological chemistry2011
Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2).
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 120 citations in OpenAlex.
- Article
- Exploring LRRK2-dependent Mechanisms in Parkinson's Disease Therapy.CNS & neurological disorders drug targets · 2025Review
- Clearing Amyloid-Beta by Astrocytes: The Role of Rho GTPases Signaling Pathways as Potential Therapeutic Targets.Brain sciences · 2024Review
- The cellular and extracellular proteomic signature of human dopaminergic neurons carrying the LRRK2 G2019S mutation.Frontiers in neuroscience · 2024Article
- Micro-and mesoscale aspects of neurodegeneration in engineered human neural networks carrying the LRRK2 G2019S mutation.Frontiers in cellular neuroscience · 2024Article
- Article
- Overview of the Impact of Pathogenic LRRK2 Mutations in Parkinson's Disease.Biomolecules · 2023Review
- Differential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson's disease.NPJ Parkinson's disease · 2023Article
- LRRK2 regulates actin assembly for spindle migration and mitochondrial function in mouse oocyte meiosis.Journal of molecular cell biology · 2022Article
- LRRK2 decreases microglial actin dynamics by filamentous actin depolymerization and Rac1 inhibition.Animal cells and systems · 2022Article
- In silico comparative analysis of LRRK2 interactomes from brain, kidney and lung.Brain research · 2021Article
- Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases.Frontiers in cellular neuroscience · 2021Article
- Pathogenic LRRK2 requires secondary factors to induce cellular toxicity.Bioscience reports · 2020Article
- Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases.International journal of molecular sciences · 2020Review
- VIP Induces Changes in the F-/G-Actin Ratio of Schlemm's Canal Endothelium via LRRK2 Transcriptional Regulation.Investigative ophthalmology & visual science · 2020Article
- Disruption of a RAC1-centred network is associated with Alzheimer's disease pathology and causes age-dependent neurodegeneration.Human molecular genetics · 2020Article
- Review
- LRRK2 Phosphorylation, More Than an Epiphenomenon.Frontiers in neuroscience · 2020Review
- LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same.Molecular neurodegeneration · 2019Review
- A protective role for N-acylphosphatidylethanolamine phospholipase D in 6-OHDA-induced neurodegeneration.Scientific reports · 2019Article
14 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are currently the most common genetic cause of familial late-onset Parkinson disease, which is clinically indistinguishable from idiopathic disease. The most common pathological mutation in LRRK2, G2019S LRRK2, is known to cause neurite retraction. However, molecular mechanisms underlying regulation of neurite length by LRRK2 are unknown. Here, we demonstrate a novel interaction between LRRK2 and the Rho GTPase, Rac1, which plays a critical role in actin cytoskeleton remodeling necessary for the maintenance of neurite morphology. LRRK2 binds strongly to endogenous or expressed Rac1, while showing weak binding to Cdc42 and no binding to RhoA. Co-expression with LRRK2 increases Rac1 activity, as shown by increased binding to the p21-activated kinase, which modulates actin cytoskeletal dynamics. LRRK2 constructs carrying mutations that inactivate the kinase or GTPase activities do not activate Rac1. Interestingly, LRRK2 does not increase levels of membrane-bound Rac1 but dramatically changes the cellular localization of Rac1, causing polarization, which is augmented further when LRRK2 is co-expressed with constitutively active Rac1. Four different disease-related mutations in LRRK2 altered binding to Rac1, with the G2019S and R1441C LRRK2 mutations attenuating Rac1 binding and the Y1699C and I2020T LRRK2 mutations increasing binding. Co-expressing Rac1 in SH-SY5Y cells rescues the G2019S mutant phenotype of neurite retraction. We hypothesize that pathological mutations in LRRK2 attenuates activation of Rac1, causing disassembly of actin filaments, leading to neurite retraction. The interactions between LRRK2 and Rho GTPases provide a novel pathway through which LRRK2 might modulate cellular dynamics and contribute to the pathophysiology of Parkinson 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.