ArticleCurrent biology : CB2021
Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes.
Article in Current biology : CB, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers, 1 of them a synthesis that pooled it.
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Who cites it
110 citing papers in PubMed, 1 synthesis or guideline pooled it, 170 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- PPM1H loss alters intrasynaptic alpha-synuclein localization in a LRRK2-dependent manner.Molecular brain · 2026Article
- Canonical and noncanonical autophagy in immunity.Immunity · 2026Review
- Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.The Journal of clinical investigation · 2026Review
- Regulation and roles of mammalian mitophagy.Nature reviews. Molecular cell biology · 2026Review
- Article
- The MIRO1-BAX Complex Dictates Life and Death at the Mitochondrial Gate.bioRxiv : the preprint server for biology · 2026Article
- Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation.Cell reports · 2026Article
- Sleep-circadian modulation of autophagy and glymphatic function: failure of coordinated brain clearance in Parkinson's disease.NPJ Parkinson's disease · 2026Review
- Strategies for Optimizing Genetic Mouse Models to Enhance the Understanding of Parkinson's Disease.Biomedicines · 2026Review
- Axonal Transport Deficits in Parkinson's Disease: Insights from Neurotoxin, Genetic, and Sporadic Models.Brain sciences · 2026Review
- The emerging role and therapeutic targeting of autophagy-lysosome pathway in the pathogenesis of Parkinson's disease.Translational neurodegeneration · 2026Review
- TBK1 activity regulates the directionality of axonal transport of signalling endosomes.Life science alliance · 2026Article
- Disruption of Synaptic Vesicle Trafficking in Alzheimer's and Parkinson's Disease: Mechanisms and Therapeutic Implication.International journal of molecular sciences · 2026Review
- Role of LRRK2 in physiological activities, diseases, and therapy.Chinese medical journal · 2026Review
- A Syd and RUFY dynein adaptor complex mediates axonal circulation of dense core vesicles.The Journal of cell biology · 2026Article
- OPA1 Deficiency Impairs NGF Signaling and Drives Sympathetic Neurodegeneration.JACC. Basic to translational science · 2026Article
- The Role of the Golgi Apparatus in Neurodegeneration.Sub-cellular biochemistry · 2026Review
- Autophagy-lysosomal pathway in neurodegeneration.Molecular neurodegeneration advances · 2026Review
- The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.Scientific reports · 2025Article
50 more citing papers are in PubMed but not listed here.
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5 authors at 1 institution in 1 country.
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Abstract
Parkinson's disease-causing mutations in the leucine-rich repeat kinase 2 (LRRK2) gene hyperactivate LRRK2 kinase activity and cause increased phosphorylation of Rab GTPases, important regulators of intracellular trafficking. We found that the most common LRRK2 mutation, LRRK2-G2019S, dramatically reduces the processivity of autophagosome transport in neurons in a kinase-dependent manner. This effect was consistent across an overexpression model, neurons from a G2019S knockin mouse, and human induced pluripotent stem cell (iPSC)-derived neurons gene edited to express the G2019S mutation, and the effect was reversed by genetic or pharmacological inhibition of LRRK2. Furthermore, LRRK2 hyperactivation induced by overexpression of Rab29, a known activator of LRRK2 kinase, disrupted autophagosome transport to a similar extent. Mechanistically, we found that hyperactive LRRK2 recruits the motor adaptor JNK-interacting protein 4 (JIP4) to the autophagosomal membrane, inducing abnormal activation of kinesin that we propose leads to an unproductive tug of war between anterograde and retrograde motors. Disruption of autophagosome transport correlated with a significant defect in autophagosome acidification, suggesting that the observed transport deficit impairs effective degradation of autophagosomal cargo in neurons. Our results robustly link increased LRRK2 kinase activity to defects in autophagosome transport and maturation, further implicating defective autophagy in the pathogenesis of Parkinson's 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.