ArticleHuman molecular genetics2017
LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers, 1 of them a synthesis that pooled it.
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Who cites it
70 citing papers in PubMed, 1 synthesis or guideline pooled it, 103 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- Long-read sequencing enables high-accuracy mitochondrial heteroplasmy detection in Parkinson's disease.BMC genomics · 2026Article
- Machine learning image analysis predicts Parkinson disease genotype and mitochondrial lysosomal abnormalities in iPS neurons.NPJ Parkinson's disease · 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
- Rab12 is a regulator of mitophagy and mitochondrial homeostasis.bioRxiv : the preprint server for biology · 2026Article
- Parkinson's disease linked LRRK2 G2019S drives oxidative nuclear DNA damage and PARP1 hyperactive signaling.bioRxiv : the preprint server for biology · 2026Article
- Multilayered interplay between the cGAS-STING pathway and autophagy.Autophagy reports · 2026Review
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- Leucine-rich repeat kinase 2 biomarkers for Parkinson's disease.The Biochemical journal · 2025Review
- LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.The Biochemical journal · 2025Review
- The Multifaceted Role of LRRK2 in Parkinson's Disease.Brain sciences · 2025Review
- Transcriptome signatures of human neural stem cells derived from LRRK2 gene therapeutic cells.Scientific reports · 2025Article
- Selective dopaminergic neurotoxicity modulated by inherent cell-type specific neurobiology.Neurotoxicology · 2024Review
- G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage.NPJ Parkinson's disease · 2024Article
- A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells.NPJ Parkinson's disease · 2024Article
- Advancements in Genetic and Biochemical Insights: Unraveling the Etiopathogenesis of Neurodegeneration in Parkinson's Disease.Biomolecules · 2024Review
- Inactive S. aureus Cas9 downregulates alpha-synuclein and reduces mtDNA damage and oxidative stress levels in human stem cell model of Parkinson's disease.Scientific reports · 2023Article
- A blood-based marker of mitochondrial DNA damage in Parkinson's disease.Science translational medicine · 2023Article
- Axonal energy metabolism, and the effects in aging and neurodegenerative diseases.Molecular neurodegeneration · 2023Review
10 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
10 authors at 4 institutions in 1 country.
Funding
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with increased risk for developing Parkinson's disease (PD). Previously, we found that LRRK2 G2019S mutation carriers have increased mitochondrial DNA (mtDNA) damage and after zinc finger nuclease-mediated gene mutation correction, mtDNA damage was no longer detectable. While the mtDNA damage phenotype can be unambiguously attributed to the LRRK2 G2019S mutation, the underlying mechanism(s) is unknown. Here, we examine the role of LRRK2 kinase function in LRRK2 G2019S-mediated mtDNA damage, using both genetic and pharmacological approaches in cultured neurons and PD patient-derived cells. Expression of LRRK2 G2019S induced mtDNA damage in primary rat midbrain neurons, but not in cortical neuronal cultures. In contrast, the expression of LRRK2 wild type or LRRK2 D1994A mutant (kinase dead) had no effect on mtDNA damage in either midbrain or cortical neuronal cultures. In addition, human LRRK2 G2019S patient-derived lymphoblastoid cell lines (LCL) demonstrated increased mtDNA damage relative to age-matched controls. Importantly, treatment of LRRK2 G2019S expressing midbrain neurons or patient-derived LRRK2 G2019S LCLs with the LRRK2 kinase inhibitor GNE-7915, either prevented or restored mtDNA damage to control levels. These findings support the hypothesis that LRRK2 G2019S-induced mtDNA damage is LRRK2 kinase activity dependent, uncovering a novel pathological role for this kinase. Blocking or reversing mtDNA damage via LRRK2 kinase inhibition or other therapeutic approaches may be useful to slow PD-associated pathology.
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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.