ArticleProceedings of the National Academy of Sciences of the United States of America2018
LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson's disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers, 2 of them syntheses that pooled it.
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Who cites it
114 citing papers in PubMed, 2 syntheses or guidelines pooled it, 159 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Emerging links between pediatric lysosomal storage diseases and adult parkinsonism.Movement disorders : official journal of the Movement Disorder Society · 2019Pooled it
- Oxidative stress in neurodegeneration: from a simple insult to a dynamic regulator.Redox report : communications in free radical research · 2026Review
- Synaptic Proteostasis in Health and Disease.Journal of neurochemistry · 2026Review
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Article
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Dysregulation of astrocytic DNAJC6 contributes to sporadic Parkinson's disease pathogenesis.The Journal of clinical investigation · 2026Article
- DNAJC6 Parkinson's disease: Endolysosomal dysfunction and emerging roles for oligodendrocytes.NPJ Parkinson's disease · 2026Review
- N-acetyl-l-leucine lowers α-synuclein levels and improves synaptic function in Parkinson's disease models.The Journal of clinical investigation · 2026Article
- Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson's disease.Nature cell biology · 2026Article
- Clathrin-mediated endocytosis as an axis for the etiopathogenesis of Parkinson's disease.Journal of cell science · 2026Review
- In vivo Proximity & Spatial Proteomics with CRISPR Screening Identify STXBP1 as a Protective Modifier of α-synuclein Toxicity in Dopamine Neurons.bioRxiv : the preprint server for biology · 2026Article
- LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal toxicity via phosphorylation within its lipid-sensing ALPS2 motif.bioRxiv : the preprint server for biology · 2026Article
- LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal integrity via phosphorylation within its lipid-sensing ALPS2 motif.Frontiers in molecular neuroscience · 2026Article
- The G2019S LRRK2 mutation exacerbates α-synuclein and tau neuropathology through divergent pathways in Parkinson's disease models.Acta neuropathologica · 2025Article
- LRRK2 and the fragile synapse: a molecular prelude to Parkinson's disease?The Biochemical journal · 2025Review
- An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.iScience · 2025Article
- Low-frequency genetic variants in GAK enhance Golgi function and protect against Parkinson's disease.medRxiv : the preprint server for health sciences · 2025Article
- Role of LRRK2 in axonal transport and Parkinson's disease.The Biochemical journal · 2025Review
54 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Recently identified Parkinson's disease (PD) genes involved in synaptic vesicle endocytosis, such as DNAJC6 (auxilin), have further implicated synaptic dysfunction in PD pathogenesis. However, how synaptic dysfunction contributes to the vulnerability of human dopaminergic neurons has not been previously explored. Here, we demonstrate that commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at Ser627. Kinase activity-dependent LRRK2 phosphorylation of auxilin led to differential clathrin binding, resulting in disrupted synaptic vesicle endocytosis and decreased synaptic vesicle density in LRRK2 patient-derived dopaminergic neurons. Moreover, impaired synaptic vesicle endocytosis contributed to the accumulation of oxidized dopamine that in turn mediated pathogenic effects such as decreased glucocerebrosidase activity and increased α-synuclein in mutant LRRK2 neurons. Importantly, these pathogenic phenotypes were partially attenuated by restoring auxilin function in mutant LRRK2 dopaminergic neurons. Together, this work suggests that mutant LRRK2 disrupts synaptic vesicle endocytosis, leading to altered dopamine metabolism and dopamine-mediated toxic effects in patient-derived dopaminergic neurons.
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Registered trials
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