ArticleHuman molecular genetics2016
14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 82 citations in OpenAlex.
- Chemical Genetic Targeting of the LRRK2 GTPase Domain.bioRxiv : the preprint server for biology · 2026Article
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Regulation between LRRK2 and PP2A signaling in cellular models of Parkinson's disease.The Biochemical journal · 2026Article
- 14-3-3θ phosphorylation at S232 reduces its interactome and regulates axonal trafficking.Disease models & mechanisms · 2025Article
- 14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.Journal of neurochemistry · 2025Article
- A novel 14-3-3θ phosphomimetic mouse model demonstrates social dominance defects.Biology open · 2025Article
- 14-3-3 phosphorylation inhibits 14-3-3θ's ability to regulate LRRK2 kinase activity and toxicity.Human molecular genetics · 2024Article
- Fragment-Based Interrogation of the 14-3-3/TAZ Protein-Protein Interaction.Biochemistry · 2024Article
- Chronic stress dysregulates the Hippo/YAP/14-3-3η pathway and induces mitochondrial damage in basolateral amygdala in a mouse model of depression.Theranostics · 2024Article
- How Parkinson's Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types.Journal of Parkinson's disease · 2024Review
- 14-3-3 proteins-a moonlight protein complex with therapeutic potential in neurological disorder: in-depth review with Alzheimer's disease.Frontiers in molecular biosciences · 2024Review
- Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments.Journal of the American Chemical Society · 2023Article
- Promising biomarkers and therapeutic targets for the management of Parkinson's disease: recent advancements and contemporary research.Metabolic brain disease · 2023Review
- The parkinsonian LRRK2 R1441G mutation shows macroautophagy-mitophagy dysregulation concomitant with endoplasmic reticulum stress.Cell biology and toxicology · 2022Article
- Exploring the focal role of LRRK2 kinase in Parkinson's disease.Environmental science and pollution research international · 2022Review
- Article
- LRRK2 and idiopathic Parkinson's disease.Trends in neurosciences · 2022Review
- Emerging Therapeutic Strategies for Parkinson's Disease and Future Prospects: A 2021 Update.Biomedicines · 2022Review
- Pathways to Parkinson's disease: a spotlight on 14-3-3 proteins.NPJ Parkinson's disease · 2021Review
- Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
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Authors and funding
5 authors at 1 institution in 1 country.
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Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Parkinson's disease (PD), and LRRK2 is a risk factor for idiopathic PD. How LRRK2 function is regulated is not well understood. Recently, the highly conserved 14-3-3 proteins, which play a key role in many cellular functions including cell death, have been shown to interact with LRRK2. In this study, we investigated whether 14-3-3s can regulate mutant LRRK2-induced neurite shortening and kinase activity. In the presence of 14-3-3θ overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wild-type levels. Similarly, 14-3-3θ overexpression reversed neurite shortening in neuronal cultures from BAC transgenic R1441G-LRRK2 mice. Conversely, inhibition of 14-3-3s by the pan-14-3-3 inhibitor difopein or dominant-negative 14-3-3θ further reduced neurite length in G2019S-LRRK2 cultures. Since G2019S-LRRK2 toxicity is likely mediated through increased kinase activity, we examined 14-3-3θ's effects on LRRK2 kinase activity. 14-3-3θ overexpression reduced the kinase activity of G2019S-LRRK2, while difopein promoted the kinase activity of G2019S-LRRK2. The ability of 14-3-3θ to reduce LRRK2 kinase activity required direct binding of 14-3-3θ with LRRK2. The potentiation of neurite shortening by difopein in G2019S-LRRK2 neurons was reversed by LRRK2 kinase inhibitors. Taken together, we conclude that 14-3-3θ can regulate LRRK2 and reduce the toxicity of mutant LRRK2 through a reduction of kinase activity.
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