ArticleMolecular neurodegeneration2011
Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation.
Article in Molecular neurodegeneration, 2011. 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.
- Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.Stem cell reviews and reports · 2026Review
- Oxidative signaling thresholds shape vulnerability in the central and peripheral nervous systems.PLoS biology · 2026Article
- Enzymatic/Mitochondrial Import Bottleneck in Sepsis with Possible Extensions to DIC: IV Glutathione and Hinokitiol as Potential Therapeutic Candidates.International journal of molecular sciences · 2026Article
- High molecular weight insoluble parkin in the substantia nigra of patients with idiopathic Parkinson's disease.NPJ Parkinson's disease · 2026Article
- Cleaving Expectations: A Review of Proteasome Functional and Catalytic Diversity.Biomolecules · 2025Review
- p22Nature cardiovascular research · 2025Article
- Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.Biochemical Society transactions · 2025Review
- Mechanisms and regulation of substrate degradation by the 26S proteasome.Nature reviews. Molecular cell biology · 2025Review
- Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases.Frontiers in pharmacology · 2025Review
- MANF facilitates breast cancer cell survival under glucose-starvation conditions via PRKN-mediated mitophagy regulation.Autophagy · 2025Article
- Redox regulation, protein S-nitrosylation, and synapse loss in Alzheimer's and related dementias.Neuron · 2024Review
- Chitosan biomineralized with ions-doped nano-hydroxyapatite tunes osteoblasts metabolism and DNA damage.Journal of biological engineering · 2024Article
- Multifaceted Proteome Analysis at Solubility, Redox, and Expression Dimensions for Target Identification.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Diverse Functions of Parkin in Midbrain Dopaminergic Neurons.Movement disorders : official journal of the Movement Disorder Society · 2024Review
- Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis.Antioxidants (Basel, Switzerland) · 2024Review
- Expanding the genetic and phenotypic spectrum of TRAPPC9 and MID2-related neurodevelopmental disabilities: report of two novel mutations, 3D-modelling, and molecular docking studies.Journal of human genetics · 2024Article
- Protein Oxidative Modifications in Neurodegenerative Diseases: From Advances in Detection and Modelling to Their Use as Disease Biomarkers.Antioxidants (Basel, Switzerland) · 2024Review
- Current Technologies Unraveling the Significance of Post-Translational Modifications (PTMs) as Crucial Players in Neurodegeneration.Biomolecules · 2024Review
- History of Parkinson's Disease-Associated Gene,International journal of molecular sciences · 2023Review
- The evolution of selective autophagy as a mechanism of oxidative stress response: The evolutionarily acquired ability of selective autophagy receptors to respond to oxidative stress is beneficial for human longevity.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023Review
36 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundAccumulation of aberrant proteins to form Lewy bodies (LBs) is a hallmark of Parkinson's disease (PD). Ubiquitination-mediated degradation of aberrant, misfolded proteins is critical for maintaining normal cell function. Emerging evidence suggests that oxidative/nitrosative stress compromises the precisely-regulated network of ubiquitination in PD, particularly affecting parkin E3 ligase activity, and contributes to the accumulation of toxic proteins and neuronal cell death.
resultsTo gain insight into the mechanism whereby cell stress alters parkin-mediated ubiquitination and LB formation, we investigated the effect of oxidative stress. We found significant increases in oxidation (sulfonation) and subsequent aggregation of parkin in SH-SY5Y cells exposed to the mitochondrial complex I inhibitor 1-methyl-4-phenlypyridinium (MPP+), representing an in vitro cell-based PD model. Exposure of these cells to direct oxidation via pathological doses of H2O2 induced a vicious cycle of increased followed by decreased parkin E3 ligase activity, similar to that previously reported following S-nitrosylation of parkin. Pre-incubation with catalase attenuated H2O2 accumulation, parkin sulfonation, and parkin aggregation. Mass spectrometry (MS) analysis revealed that H2O2 reacted with specific cysteine residues of parkin, resulting in sulfination/sulfonation in regions of the protein similar to those affected by parkin mutations in hereditary forms of PD. Immunohistochemistry or gel electrophoresis revealed an increase in aggregated parkin in rats and primates exposed to mitochondrial complex I inhibitors, as well as in postmortem human brain from patients with PD with LBs.
conclusionThese findings show that oxidative stress alters parkin E3 ligase activity, leading to dysfunction of the ubiquitin-proteasome system and potentially contributing to LB formation.
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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.