ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 124 citations in OpenAlex.
- Molecular programs in human locus coeruleus link APOE and neuromelanin to Alzheimer's vulnerability.Acta neuropathologica · 2026Article
- The role of ATF4 in neurons under mitochondrial stress.NAR genomics and bioinformatics · 2026Article
- Role of Activating Transcription Factor 4 in Metabolic, Neurologic, and Ocular Diseases.Cells · 2026Review
- The dual role of ATF4 in neurons: from stress adaptation to therapeutic intervention.Frontiers in molecular neuroscience · 2026Review
- Epigenetic Mechanisms Shaping Spine Regulation: Unveiling the Role of Cytoskeletal Dynamics and Localized Protein Synthesis.Molecular neurobiology · 2025Review
- Impact of Alzheimer's disease risk factors and local neuromelanin content on the transcriptomic landscape of the human locus coeruleus.bioRxiv : the preprint server for biology · 2025Article
- The integrated stress response in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
- ISR Modulators in Neurological Diseases.Current neuropharmacology · 2025Review
- The integrated stress response in brain diseases: A double-edged sword for proteostasis and synapses.Current opinion in neurobiology · 2024Review
- IRE1/JNK Is the Leading UPR Pathway in 6-OHDA-Induced Degeneration of Differentiated SH-SY5Y Cells.International journal of molecular sciences · 2024Article
- PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.Cellular and molecular life sciences : CMLS · 2024Review
- Midnolin, a Genetic Risk Factor for Parkinson's Disease, Promotes Neurite Outgrowth Accompanied by Early Growth Response 1 Activation in PC12 Cells.Molecular and cellular biology · 2024Article
- The PERK pathway: beneficial or detrimental for neurodegenerative diseases and tumor growth and cancer.Human molecular genetics · 2023Review
- Mitochondrial stress induces hepatic stellate cell activation in response to the ATF4/TRIB3 pathway stimulation.Journal of gastroenterology · 2023Article
- CREB3L2-ATF4 heterodimerization defines a transcriptional hub of Alzheimer's disease gene expression linked to neuropathology.Science advances · 2023Article
- Attenuation of Piwil2 induced by hypoxic postconditioning prevents cerebral ischemic injury by inhibiting CREB2 promoter methylation.Brain pathology (Zurich, Switzerland) · 2023Article
- Recovery Sleep Immediately after Prolonged Sleep Deprivation Stimulates the Transcription of Integrated Stress Response-Related Genes in the Liver of Male Rats.Clocks & sleep · 2022Article
- Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells.Neuron · 2022Article
- Sleep deficiency as a driver of cellular stress and damage in neurological disorders.Sleep medicine reviews · 2022Review
- The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress.International journal of molecular sciences · 2022Review
19 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder, for which there are no effective disease-modifying therapies. The transcription factor ATF4 (activating transcription factor 4) is induced by multiple PD-relevant stressors, such as endoplasmic reticulum stress and oxidative damage. ATF4 may exert either protective or deleterious effects on cell survival, depending on the paradigm. However, the role of ATF4 in the pathogenesis of PD has not been explored. We find that ATF4 levels are increased in neuromelanin-positive neurons in the substantia nigra of a subset of PD patients relative to controls. ATF4 levels are also upregulated in neuronal PC12 cells treated with the dopaminergic neuronal toxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+). To explore the role of ATF4 in cell survival in PD-relevant contexts, we either silenced or overexpressed ATF4 in cellular models of PD. In neuronal PC12 cells, silencing of ATF4 enhanced cell death in response to either 6-OHDA or MPP+. Conversely, overexpression of ATF4 reduced cell death caused by dopaminergic neuronal toxins. ATF4 was also protective against 6-OHDA-induced death of cultured mouse ventral midbrain dopaminergic neurons. We further show that parkin, a gene associated with autosomal recessive PD, plays a critical role in ATF4-mediated protection. After treatment with 6-OHDA or MPP+, parkin protein levels fall, despite an increase in mRNA levels. ATF4 silencing exacerbates the toxin-induced reduction of parkin, whereas ATF4 overexpression partially preserves parkin levels. Finally, parkin silencing blocked the protective capacity of ATF4. These results indicate that ATF4 plays a protective role in PD through the regulation of parkin.
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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.