ArticleHuman molecular genetics2019
Mitochondrial clearance and maturation of autophagosomes are compromised in LRRK2 G2019S familial Parkinson's disease patient fibroblasts.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 66 citations in OpenAlex.
- Neuroinflammatory and Motor Alterations in LRRK2*G2019S Transgenic Mice Without Enhanced Vulnerability to Aging or Chronic MPTP-Induced Nigrostriatal Neurodegeneration.Journal of neurochemistry · 2026Article
- VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.Brain : a journal of neurology · 2026Article
- LRRK2 I1371V Mutation Drives Astrocytic Glucose Metabolism Failure and Induces Integrated ER-Mitochondria-Lysosome Dysfunction in Parkinson's Disease.International journal of molecular sciences · 2026Article
- Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- Unveiling Exosomes and Microvesicles in Parkinson's Disease: Mechanistic Insights Into Cell Death Pathways and Therapeutic Potential.Molecular neurobiology · 2025Review
- Therapeutic targeting of alternative splicing caused by a lethal noncoding structural variant in X-linked dystonia parkinsonism.medRxiv : the preprint server for health sciences · 2025Article
- LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.The Biochemical journal · 2025Review
- Leucine-rich repeat kinase 2 biomarkers for Parkinson's disease.The Biochemical journal · 2025Review
- Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson's Disease with Potential Therapeutic Implications.Biomolecules · 2025Review
- Intervention strategies for Parkinson's disease: the role of exercise and mitochondria.Frontiers in aging neuroscience · 2025Review
- Neuronal threshold functions: Determining symptom onset in neurological disorders.Progress in neurobiology · 2024Review
- LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants.Neurobiology of disease · 2024Article
- G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage.NPJ Parkinson's disease · 2024Article
- STING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges.Neuron · 2024Review
- Splice-switching antisense oligonucleotides for pediatric neurological disorders.Frontiers in molecular neuroscience · 2024Review
- ASO-mediated knockdown or kinase inhibition ofMolecular therapy. Nucleic acids · 2023Article
- Article
- Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models.Human molecular genetics · 2023Article
- Outlook of PINK1/Parkin signaling in molecular etiology of Parkinson's disease, with insights intoZoological research · 2023Review
- An Efficient 2D Protocol for Differentiation of iPSCs into Mature Postmitotic Dopaminergic Neurons: Application for Modeling Parkinson's Disease.International journal of molecular sciences · 2023Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
This study utilized human fibroblasts as a preclinical discovery and diagnostic platform for identification of cell biological signatures specific for the LRRK2 G2019S mutation producing Parkinson's disease (PD). Using live cell imaging with a pH-sensitive Rosella biosensor probe reflecting lysosomal breakdown of mitochondria, mitophagy rates were found to be decreased in fibroblasts carrying the LRRK2 G2019S mutation compared to cells isolated from healthy subject (HS) controls. The mutant LRRK2 increased kinase activity was reduced by pharmacological inhibition and targeted antisense oligonucleotide treatment, which normalized mitophagy rates in the G2019S cells and also increased mitophagy levels in HS cells. Detailed mechanistic analysis showed a reduction of mature autophagosomes in LRRK2 G2019S fibroblasts, which was rescued by LRRK2 specific kinase inhibition. These findings demonstrate an important role for LRRK2 protein in regulation of mitochondrial clearance by the lysosomes, which is hampered in PD with the G2019S mutation. The current results are relevant for cell phenotypic diagnostic approaches and potentially for stratification of PD patients for targeted therapy.
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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.