ArticleMolecular neurobiology2019
Loss of Microglial Parkin Inhibits Necroptosis and Contributes to Neuroinflammation.
Article in Molecular neurobiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 61 citations in OpenAlex.
- AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.Journal of physiology and biochemistry · 2026Review
- Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.Aging · 2025Review
- Activation of ZBP1/RIPK3/MLKL-Dependent Necroptosis by Pseudorabies Virus Restricts Viral Infection in BV2 Microglia Cells.Transboundary and emerging diseases · 2025Article
- From pathogenesis to treatment: the emerging role of ferroptosis in Parkinson's disease.Frontiers in immunology · 2025Review
- Mitophagy-related regulated cell death: molecular mechanisms and disease implications.Cell death & disease · 2024Review
- In and out: Benchmarking in vitro, in vivo, ex vivo, and xenografting approaches for an integrative brain disease modeling pipeline.Stem cell reports · 2024Review
- NLRX1 Inhibits LPS-Induced Microglial Death via Inducing p62-Dependent HO-1 Expression, Inhibiting MLKL and Activating PARP-1.Antioxidants (Basel, Switzerland) · 2024Article
- What Can Inflammation Tell Us about Therapeutic Strategies for Parkinson's Disease?International journal of molecular sciences · 2024Review
- Article
- Novel Insights into Parkin-Mediated Mitochondrial Dysfunction and "Mito-Inflammation" in α-Synuclein Toxicity. The Role of the cGAS-STING Signalling Pathway.Journal of inflammation research · 2024Review
- The Role of Ubiquitin-Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease.Neuromolecular medicine · 2023Review
- The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson's Disease.Neuromolecular medicine · 2023Review
- The Interplay Between Autophagy and Regulated Necrosis.Antioxidants & redox signaling · 2023Review
- Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson's disease.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2023Review
- Neuroprotective Effects of a Cholecystokinin Analogue in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Parkinson's Disease Mouse Model.Frontiers in neuroscience · 2022Article
- Mechanisms of Autoimmune Cell in DA Neuron Apoptosis of Parkinson's Disease: Recent Advancement.Oxidative medicine and cellular longevity · 2022Review
- Transcriptional and epigenetic regulation of microglia in maintenance of brain homeostasis and neurodegeneration.Frontiers in molecular neuroscience · 2022Review
- Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice.Cell death discovery · 2021Article
- Preclinical Evidence for the Interplay between Oxidative Stress and RIP1-Dependent Cell Death in Neurodegeneration: State of the Art and Possible Therapeutic Implications.Antioxidants (Basel, Switzerland) · 2021Review
- Aging-Dependent Mitophagy Dysfunction in Alzheimer's Disease.Molecular neurobiology · 2021Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Parkin is an E3 ubiquitin ligase involved in Parkinson's disease (PD). Necroptosis is a regulated form of cell death that depends on receptor interacting protein 1 (RIP1) and 3 (RIP3). Importantly, parkin has been implicated in ubiquitination events that can alter inflammation and necroptosis. Here, we investigated how parkin influences microglial function. Incubation of BV-2 microglial cells with zVAD.fmk (zVAD) induced high levels of cell death and viability loss, while N9 microglial cells and primary microglia required further stimuli. Importantly, necrostatin-1 (Nec-1), an inhibitor of RIP1 kinase activity, abrogated cell death, thus implicating RIP1-dependent necroptosis in cell death. Cell death was characterized by necrosome assembly, as determined by sequestration of RIP1/RIP3 in insoluble fractions and by MLKL phosphorylation, which were all abolished by Nec-1. Also, necroptosis-inducing conditions led to TNF-α secretion, which may in turn contribute to autocrine necroptosis activation. Interestingly, parkin knockdown protected BV-2 cells from zVAD-induced necroptosis, which may depend on the higher RIP1 ubiquitination levels detected in siRNA-PARK2 transfected cells. This effect was independent of inflammation, since pro-inflammatory stimulation of BV-2 and primary microglia with silenced parkin resulted in stronger pro-inflammatory gene expression, an opposite observation from zVAD-exposed BV-2 cells. LPS-mediated inflammation was exacerbated by NF-κB/JNK over-activation. Finally, no alterations in mitochondrial ROS production were detected in any condition, thereby excluding the role of parkin in mitophagy. In conclusion, here, we reveal that parkin may have unsuspected roles in microglia by modulating ubiquitination. Parkin loss exacerbates inflammation and promotes survival of activated microglia, thus contributing to chronic neuroinflammation.
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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.