ArticleMolecular neurodegeneration2021
Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo.
Article in Molecular neurodegeneration, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 1 of them a synthesis that pooled it.
What it found
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Who cites it
8 citing papers in PubMed, 1 synthesis or guideline pooled it, 14 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- In vivo and in silico models of Drosophila for Parkinson's disease.The FEBS journal · 2025Review
- Dopamine Toxicity Induces ROS-Dependent Death of Murine Neuroblastoma Cells: Impact on the Interactions of Cofilin With UCHL1 and MMP9.Neurochemical research · 2025Article
- Biotin mitigates the development of manganese-induced, Parkinson's disease-related neurotoxicity inScience signaling · 2025Article
- Comparative Proteomics Highlights that GenX Exposure Leads to Metabolic Defects and Inflammation in Astrocytes.Environmental science & technology · 2024Article
- Genetic modifiers of synucleinopathies-lessons from experimental models.Oxford open neuroscience · 2023Review
- Roles of α-Synuclein and Disease-Associated Factors inInternational journal of molecular sciences · 2022Review
- Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundMutations in LRRK2 are the most common cause of familial Parkinson's disease and typically cause disease in the context of abnormal aggregation and deposition of α-synuclein within affected brain tissue.
methodsWe combine genetic analysis of Lrrk-associated toxicity in a penetrant Drosophila model of wild type human α-synuclein neurotoxicity with biochemical analyses and modeling of LRRK2 toxicity in human neurons and transgenic mouse models.
resultsWe demonstrate that Lrrk and α-synuclein interact to promote neuronal degeneration through convergent effects on the actin cytoskeleton and downstream dysregulation of mitochondrial dynamics and function. We find specifically that monomers and dimers of Lrrk efficiently sever actin and promote normal actin dynamics in vivo. Oligomerization of Lrrk, which is promoted by dominant Parkinson's disease-causing mutations, reduces actin severing activity in vitro and promotes excess stabilization of F-actin in vivo. Importantly, a clinically protective Lrrk mutant reduces oligomerization and α-synuclein neurotoxicity.
conclusionsOur findings provide a specific mechanistic link between two key molecules in the pathogenesis of Parkinson's disease, α-synuclein and LRRK2, and suggest potential new approaches for therapy development.
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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.