ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2017
Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
89 citing papers in PubMed, 2 syntheses or guidelines pooled it, 120 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- Asymmetric distribution of mitochondrial CaExperimental & molecular medicine · 2026Article
- The role of mitochondrial Na⁺/Ca²⁺ exchanger in brain cell aging.Journal of bioenergetics and biomembranes · 2026Review
- Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer's disease progression.The EMBO journal · 2026Article
- Zebrafish Models of Parkinson's Disease: From Pathogenesis to Drug Discovery.International journal of molecular sciences · 2026Review
- A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage.bioRxiv : the preprint server for biology · 2026Article
- Role of LRRK2 in physiological activities, diseases, and therapy.Chinese medical journal · 2026Review
- The embedding of stress: mitophagy as a mechanism for the central nervous system (CNS) programming and lifelong disease vulnerability.Frontiers in cell and developmental biology · 2026Review
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- Cell-Free DNA and Mitochondria in Parkinson's Disease.International journal of molecular sciences · 2025Review
- Role of Mitochondrial Calcium Dysregulation in Alzheimer's Disease Pathogenesis.Molecular neurobiology · 2025Review
- Role of mitochondrial CaMolecular medicine reports · 2025Review
- LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.The Biochemical journal · 2025Review
- The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.Autophagy reports · 2025Article
- CK and LRRK2 Involvement in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Loss of mitochondrial CaCell communication and signaling : CCS · 2024Article
- Review
- Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.Aging and disease · 2024Review
- Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?Antioxidants (Basel, Switzerland) · 2024Review
29 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
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs before the well-characterized phenotype of dendritic shortening. As mitochondria play a major role in the rapid buffering of cytosolic calcium, we hypothesized that altered mitochondrial calcium handling contributes to dendritic retraction elicited by the LRRK2-G2019S and -R1441C mutations. In primary mouse cortical neurons, we observed increased depolarization-induced mitochondrial calcium uptake. We found that expression of mutant LRRK2 elicited transcriptional upregulation of the mitochondrial calcium uniporter (MCU) and the mitochondrial calcium uptake 1 protein (MICU1) with no change in levels of the mitochondrial calcium antiporter NCLX. Elevated MCU and MICU1 were also observed in LRRK2-mutated patient fibroblasts, along with increased mitochondrial calcium uptake, and in postmortem brains of sporadic PD/PDD patients of both sexes. Transcriptional upregulation of MCU and MICU1 was caused by activation of the ERK1/2 (MAPK3/1) pathway. Inhibiting ERK1/2 conferred protection against mutant LRRK2-induced neurite shortening. Pharmacological inhibitors or RNAi knockdown of MCU attenuated mitochondrial calcium uptake and dendritic/neuritic shortening elicited by mutant LRRK2, whereas expression of a constitutively active mutant of NCLX that enhances calcium export from mitochondria was neuroprotective. These data suggest that an increased susceptibility to mitochondrial calcium dysregulation contributes to dendritic injury in mutant LRRK2 pathogenesis.
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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 Socratic graph.