ArticleThe Journal of biological chemistry2011
Early and late events induced by polyQ-expanded proteins: identification of a common pathogenic property of polYQ-expanded proteins.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 66 citations in OpenAlex.
- The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease.Cell death & disease · 2024Review
- Hyperbaric Oxygen Therapy Attenuated the Motor Coordination and Cognitive Impairment of Polyglutamine Spinocerebellar Ataxia SCA17 Mice.Cerebellum (London, England) · 2024Article
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- ReducedAntioxidants (Basel, Switzerland) · 2023Article
- Polyglutamine Expansion in Huntingtin and Mechanism of DNA Damage Repair Defects in Huntington's Disease.Frontiers in cellular neuroscience · 2022Review
- Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders.Oxidative medicine and cellular longevity · 2022Review
- Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases.Antioxidants (Basel, Switzerland) · 2021Review
- Stress granules, RNA-binding proteins and polyglutamine diseases: too much aggregation?Cell death & disease · 2021Review
- Therapeutic roles of natural remedies in combating hereditary ataxia: A systematic review.Chinese medicine · 2021Review
- Nicotinamide Adenine Dinucleotide Phosphate Oxidases Are Everywhere in Brain Disease, but Not in Huntington's Disease?Frontiers in aging neuroscience · 2021Review
- Molecular and Cellular Mechanisms Affected in ALS.Journal of personalized medicine · 2020Review
- Interaction of Oxidative Stress and Misfolded Proteins in the Mechanism of Neurodegeneration.Life (Basel, Switzerland) · 2020Review
- Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery.Redox biology · 2020Article
- Deficiency in classical nonhomologous end-joining-mediated repair of transcribed genes is linked to SCA3 pathogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Exploring the role of high-mobility group box 1 (HMGB1) protein in the pathogenesis of Huntington's disease.Journal of molecular medicine (Berlin, Germany) · 2020Review
- Determining the Fate of Neurons in SCA3: ATX3, a Rising Decision Maker in Response to DNA Stresses and Beyond.Frontiers in cell and developmental biology · 2020Review
- Article
- PRAS40 alleviates neurotoxic prion peptide-induced apoptosis via mTOR-AKT signaling.CNS neuroscience & therapeutics · 2017Article
- Spinocerebellar Ataxia Type 2 Is Associated with the Extracellular Loss of Superoxide Dismutase but Not Catalase Activity.Frontiers in neurology · 2017Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
To find a common pathogenetic trait induced by polyQ-expanded proteins, we have used a conditional expression system in PC12 cells to tune the expression of these proteins and analyze the early and late consequences of their expression. We find that expression for 3 h of a polyQ-expanded protein stimulates cellular reactive oxygen species (ROS) levels and significantly reduces the mitochondrial electrochemical gradient. 24-36 h later, ROS induce DNA damage and activation of the checkpoint kinase, ATM. DNA damage signatures are reversible and persist as long as polyQ-expanded proteins are expressed. Transcription of neural and stress response genes is down-regulated in these cells. Selective inhibition of ATM or histone deacetylase rescues transcription and restores the expression of silenced genes. Eventually, after 1 week, the expression of polyQ-expanded protein also induces endoplasmic reticulum stress. As to the primary mechanism responsible for ROS generation, we find that polyQ-expanded proteins, including native Ataxin-2 and Huntingtin, are selectively sequestered in the lipid raft membrane compartment and interact with gp91, the membrane NADPH-oxidase subunit. Selective inhibition of NADPH oxidase or silencing of H-Ras signaling dissolves the aggregates and eliminates DNA damage. We suggest that targeting of the polyQ-expanded proteins to the lipid rafts activates the resident NADPH oxidase. This triggers a signal linking H-Ras, ROS, and ERK1/2 that maintains and propagates the ROS wave to the nucleus. This mechanism may represent the common pathogenetic signature of all polyQ-expanded proteins independently of the specific context or the function of the native wild type protein.
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