ArticleMolecular neurobiology2018
LRRK2 Expression Is Deregulated in Fibroblasts and Neurons from Parkinson Patients with Mutations in PINK1.
Article in Molecular neurobiology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Cellular and Extracellular MicroRNA Dysregulation in LRRK2-Linked Parkinson's Disease.Molecular neurobiology · 2025Article
- Environmental Factors Exacerbate Parkinsonian Phenotypes in an Asian-Specific Knock-In LRRK2 Risk Variant in Mice.International journal of molecular sciences · 2025Article
- Altered Mitochondrial Bioenergetics and Calcium Kinetics in Young-Onset PLA2G6 Parkinson's Disease iPSCs.Journal of neurochemistry · 2025Article
- Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.Current genomics · 2025Review
- Review
- MONFIT: multi-omics factorization-based integration of time-series data sheds light on Parkinson's disease.NAR molecular medicine · 2024Article
- The Neuroanatomy of Induced Pluripotent Stem Cells: In Vitro Models of Subcortical Nuclei in Neurodegenerative Disorders.Current issues in molecular biology · 2024Review
- Multi-omics integration of scRNA-seq time series data predicts new intervention points for Parkinson's disease.Scientific reports · 2024Article
- Review
- Human Induced Pluripotent Stem Cell Phenotyping and Preclinical Modeling of Familial Parkinson's Disease.Genes · 2022Review
- Article
- Modelling Parkinson's Disease: iPSCs towards Better Understanding of Human Pathology.Brain sciences · 2021Review
- Alpha-Synuclein Aggregation in Parkinson's Disease.Frontiers in medicine · 2021Review
- Article
- Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson's Disease for Drug Identification.International journal of molecular sciences · 2020Review
- Genetic predispositions of Parkinson's disease revealed in patient-derived brain cells.NPJ Parkinson's disease · 2020Review
- A compendious summary of Parkinson's disease patient-derived iPSCs in the first decade.Annals of translational medicine · 2019Review
- SerThr-PhosphoProteome of Brain from Aged PINK1-KO+A53T-SNCA Mice Reveals pT1928-MAP1B and pS3781-ANK2 Deficits, as Hub between Autophagy and Synapse Changes.International journal of molecular sciences · 2019Article
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
Mutations in PINK1 (PARK6), a serine/threonine kinase involved in mitochondrial homeostasis, are associated with early onset Parkinson's disease. Fibroblasts from Parkinson's disease patients with compound heterozygous mutations in exon 7 (c.1488 + 1G > A; c.1252_1488del) showed no apparent signs of mitochondrial impairment. To elucidate changes primarily caused by lack of functional PINK1, we over-expressed wild-type PINK1, which induced a significant downregulation of LRRK2 (PARK8). Indeed, we found that LRRK2 protein basal levels were significantly higher in the mutant PINK1 fibroblasts. To examine the interaction between the two PARK genes in a disease-relevant cell context, we generated induced pluripotent stem cell (iPSC) lines from mutant, carrier and control fibroblasts by lentiviral-mediated re-programming. Efficiency of neural induction and dopamine differentiation using a floor-plate induction protocol was similar in all genotypes. As observed in fibroblasts, PINK1 mutant neurons showed increased LRRK2 expression both at the RNA and protein level and transient over-expression of wild-type PINK1 efficiently downregulated LRRK2 levels. Additionally, we confirmed a dysregulation of LRRK2 expression in fibroblasts from patients with a different homozygous mutation in PINK1 exon 4, c.926G > A (G309D). Thus, our results identify a novel role of PINK1 modulating the levels of LRRK2 in Parkinson's disease fibroblasts and neurons, suggest a convergent pathway for these PARK genes, and broaden the role of LRRK2 in the pathogenesis of Parkinson's disease.
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Registered trials
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