ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
84 citing papers in PubMed, 140 citations in OpenAlex.
- A toxic gain-of-function variant in MAPK8IP3 provides insights into JIP3 cellular roles.JCI insight · 2025Article
- Revolutionizing our understanding of Parkinson's disease: Dr. Heinz Reichmann's pioneering research and future research direction.Journal of neural transmission (Vienna, Austria : 1996) · 2024Review
- LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.Trends in molecular medicine · 2024Review
- Ergothioneine-Mediated Neuroprotection of Human iPSC-Derived Dopaminergic Neurons.Antioxidants (Basel, Switzerland) · 2024Article
- Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE-mediated mRNA decay in Parkinson's disease.The EMBO journal · 2023Article
- An insight into the iPSCs-derived two-dimensional culture and three-dimensional organoid models for neurodegenerative disorders.Interface focus · 2022Review
- ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function.Cell reports · 2022Article
- The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity.The Journal of cell biology · 2022Article
- Superhuman cell death detection with biomarker-optimized neural networks.Science advances · 2021Article
- Genetically encoded cell-death indicators (GEDI) to detect an early irreversible commitment to neurodegeneration.Nature communications · 2021Article
- From structure to ætiology: a new window on the biology of leucine-rich repeat kinase 2 and Parkinson's disease.The Biochemical journal · 2021Article
- The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo.International journal of molecular sciences · 2021Article
- Current State-of-the-Art and Unresolved Problems in Using Human Induced Pluripotent Stem Cell-Derived Dopamine Neurons for Parkinson's Disease Drug Development.International journal of molecular sciences · 2021Review
- Modelling Parkinson's Disease: iPSCs towards Better Understanding of Human Pathology.Brain sciences · 2021Review
- Functional genomics, genetic risk profiling and cell phenotypes in neurodegenerative disease.Neurobiology of disease · 2020Review
- Pathogenic LRRK2 requires secondary factors to induce cellular toxicity.Bioscience reports · 2020Article
- GTP-binding inhibitors increase LRRK2-linked ubiquitination and Lewy body-like inclusions.Journal of cellular physiology · 2020Article
- Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Modeling Brain Disorders Using Induced Pluripotent Stem Cells.Cold Spring Harbor perspectives in biology · 2020Review
- Autophagy in Parkinson's Disease.Journal of molecular biology · 2020Review
24 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
By combining experimental neuron models and mathematical tools, we developed a "systems" approach to deconvolve cellular mechanisms of neurodegeneration underlying the most common known cause of Parkinson's disease (PD), mutations in leucine-rich repeat kinase 2 (LRRK2). Neurons ectopically expressing mutant LRRK2 formed inclusion bodies (IBs), retracted neurites, accumulated synuclein, and died prematurely, recapitulating key features of PD. Degeneration was predicted from the levels of diffuse mutant LRRK2 that each neuron contained, but IB formation was neither necessary nor sufficient for death. Genetic or pharmacological blockade of its kinase activity destabilized LRRK2 and lowered its levels enough to account for the moderate reduction in LRRK2 toxicity that ensued. By contrast, targeting synuclein, including neurons made from PD patient-derived induced pluripotent cells, dramatically reduced LRRK2-dependent neurodegeneration and LRRK2 levels. These findings suggest that LRRK2 levels are more important than kinase activity per se in predicting toxicity and implicate synuclein as a major mediator of LRRK2-induced neurodegeneration.
Indexed as
Identifiers
What OpenQuestion holds
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.