ArticleHuman molecular genetics2012
G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers.
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Who cites it
96 citing papers in PubMed, 156 citations in OpenAlex.
- Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.Biomolecules · 2026Review
- Role of LRRK2 in physiological activities, diseases, and therapy.Chinese medical journal · 2026Review
- Investigating the ageing-Parkinson's disease nexus: standardisation of in vitro models and techniques by the PD-AGE network.NPJ Parkinson's disease · 2025Review
- Regulation of LRRK2 activity by metabolic stress and heavy metal exposure.Brain research · 2025Article
- Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson's disease.The Journal of cell biology · 2025Article
- LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.The Biochemical journal · 2025Review
- Loss of mitochondrial CaCell communication and signaling : CCS · 2024Article
- Key genes and convergent pathogenic mechanisms in Parkinson disease.Nature reviews. Neuroscience · 2024Review
- Multimodal assessment of mitochondrial function in Parkinson's disease.Brain : a journal of neurology · 2024Article
- Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models.Human molecular genetics · 2023Article
- Aging, Parkinson's Disease, and Models: What Are the Challenges?Aging biology · 2023Article
- Clinical Trial Highlights: Modulators of Mitochondrial Function.Journal of Parkinson's disease · 2023Article
- The parkinsonian LRRK2 R1441G mutation shows macroautophagy-mitophagy dysregulation concomitant with endoplasmic reticulum stress.Cell biology and toxicology · 2022Article
- Review
- Molecular mechanisms defining penetrance ofMedizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2022Article
- Regulation of Parkinson's disease-associated genes by Pumilio proteins and microRNAs in SH-SY5Y neuronal cells.PloS one · 2022Article
- Review of the epidemiology and variability of LRRK2 non-p.Gly2019Ser pathogenic mutations in Parkinson's disease.Frontiers in neuroscience · 2022Review
- The Role of Human LRRK2 in Acute Methylmercury Toxicity in Caenorhabditis elegans.Neurochemical research · 2021Article
- Article
- Nuclear and Mitochondrial Genome, Epigenome and Gut Microbiome: Emerging Molecular Biomarkers for Parkinson's Disease.International journal of molecular sciences · 2021Review
36 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
The G2019S leucine rich repeat kinase 2 (LRRK2) mutation is the most common genetic cause of Parkinson's disease (PD), clinically and pathologically indistinguishable from idiopathic PD. Mitochondrial abnormalities are a common feature in PD pathogenesis and we have investigated the impact of G2019S mutant LRRK2 expression on mitochondrial bioenergetics. LRRK2 protein expression was detected in fibroblasts and lymphoblasts at levels higher than those observed in the mouse brain. The presence of G2019S LRRK2 mutation did not influence LRRK2 expression in fibroblasts. However, the expression of the G2019S LRRK2 mutation in both fibroblast and neuroblastoma cells was associated with mitochondrial uncoupling. This was characterized by decreased mitochondrial membrane potential and increased oxygen utilization under basal and oligomycin-inhibited conditions. This resulted in a decrease in cellular ATP levels consistent with compromised cellular function. This uncoupling of mitochondrial oxidative phosphorylation was associated with a cell-specific increase in uncoupling protein (UCP) 2 and 4 expression. Restoration of mitochondrial membrane potential by the UCP inhibitor genipin confirmed the role of UCPs in this mechanism. The G2019S LRRK2-induced mitochondrial uncoupling and UCP4 mRNA up-regulation were LRRK2 kinase-dependent, whereas endogenous LRRK2 levels were required for constitutive UCP expression. We propose that normal mitochondrial function was deregulated by the expression of G2019S LRRK2 in a kinase-dependent mechanism that is a modification of the normal LRRK2 function, and this leads to the vulnerability of selected neuronal populations in PD.
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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.