ArticleScientific reports2018
A motif within the armadillo repeat of Parkinson's-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
What it found
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Regulation between LRRK2 and PP2A signaling in cellular models of Parkinson's disease.The Biochemical journal · 2026Article
- Extracellular Vesicle-Mediated Delivery of Constrained Peptides Disrupts the Pathogenic Interaction of LRRK2-FADD in Parkinson's Disease.Journal of extracellular biology · 2026Article
- Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization.ACS chemical neuroscience · 2023Article
- LRRK2 Structure-Based Activation Mechanism and Pathogenesis.Biomolecules · 2023Review
- Allosteric inhibition of LRRK2, where are we now.Biochemical Society transactions · 2020Review
- Drugena: A Fully Automated Immunoinformatics Platform for the Design of Antibody-Drug Conjugates Against Neurodegenerative Diseases.Advances in experimental medicine and biology · 2020Article
- Olive Oil Polyphenols in Neurodegenerative Pathologies.Advances in experimental medicine and biology · 2020Review
- Antibody Clustering Using a Machine Learning Pipeline that Fuses Genetic, Structural, and Physicochemical Properties.Advances in experimental medicine and biology · 2020Article
- Guilt-by-Association - Functional Insights Gained From Studying the LRRK2 Interactome.Frontiers in neuroscience · 2020Review
- Physiological and pathological roles of LRRK2 in the nuclear envelope integrity.Human molecular genetics · 2019Article
- Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform.PLoS computational biology · 2019Article
- Understanding the role of genetic variability in LRRK2 in Indian population.Movement disorders : official journal of the Movement Disorder Society · 2019Article
- Review
- LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia.PloS one · 2019Article
- Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
In experimental models, both in vivo and cellular, over-expression of Parkinson's linked mutant leucine-rich repeat kinase 2 (LRRK2) is sufficient to induce neuronal death. While several cell death associated proteins have been linked to LRRK2, either as protein interactors or as putative substrates, characterization of the neuronal death cascade remains elusive. In this study, we have mapped for the first time the domain within LRRK2 that mediates the interaction with FADD, thereby activating the molecular machinery of the extrinsic death pathway. Using homology modeling and molecular docking approaches, we have identified a critical motif within the N-terminal armadillo repeat region of LRRK2. Moreover, we show that co-expression of fragments of LRRK2 that contain the FADD binding motif, or deletion of this motif itself, blocks the interaction with FADD, and is neuroprotective. We further demonstrate that downstream of FADD, the mitochondrial proteins Bid and Bax are recruited to the death cascade and are necessary for neuronal death. Our work identifies multiple novel points within neuronal death signaling pathways that could potentially be targeted by candidate therapeutic strategies and highlight how the extrinsic pathway can be activated intracellularly in a pathogenic context.
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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.