ArticleMolecular therapy : the journal of the American Society of Gene Therapy2021
Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 40 citations in OpenAlex.
- Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.Molecular diagnosis & therapy · 2026Review
- Resilience to Endoplasmic Reticulum Stress Mitigates Membrane Hyperexcitability Underlying Late Disease Onset in a Murine Model of SCA6.Annals of neurology · 2026Article
- The Role of Crosstalk Between the Unfolded Protein Response and Autophagy in Diseases Associated with Sympathetic Nervous System Imbalance: Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Adaptive inter-tissue proteostasis networks in aging and neurodegeneration.Bioscience reports · 2026Review
- Endoplasmic reticulum stress as a mechanistic link between nutrition and inflammatory bowel disease.Frontiers in nutrition · 2026Review
- The dual role of endoplasmic reticulum stress in cerebral ischemia: from adaptive protection to apoptotic induction.Frontiers in molecular neuroscience · 2026Review
- Polyhalogenated Carbazole Impairs Dopaminergic Neurons through Dysregulation of Liquid-Liquid Phase Separation in Caenorhabditis elegans.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Environmental adversity, endoplasmic reticulum stress, and neurogenesis.Neurotoxicology · 2025Review
- Gut microbiota modulate intestinal inflammation by endoplasmic reticulum stress-autophagy-cell death signaling axis.Journal of animal science and biotechnology · 2025Review
- Endoplasmic reticulum stress in gut inflammation: Implications for ulcerative colitis and Crohn's disease.World journal of gastroenterology · 2025Review
- Homeostasis control in health and disease by the unfolded protein response.Nature reviews. Molecular cell biology · 2025Review
- The Dual Role of Survival Genes in Neurons and Cancer Cells: a Strategic Clinical Application of DX2 in Neurodegenerative Diseases and Cancer.Biomolecules & therapeutics · 2025Review
- α-Synuclein: Multiple pathogenic roles in trafficking and proteostasis pathways in Parkinson's disease.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2024Review
- Unveiling the unexplored novel signatures for osteoporosis via a detailed bioinformatics and molecular experiments based approach.American journal of translational research · 2024Article
- The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease.Progress in retinal and eye research · 2024Review
- Adaptive responses of neuronal cells to chronic endoplasmic reticulum (ER) stress.Redox biology · 2023Article
- Divergent Proteome Reactivity Influences Arm-Selective Activation of the Unfolded Protein Response by Pharmacological Endoplasmic Reticulum Proteostasis Regulators.ACS chemical biology · 2023Article
- Divergent Proteome Reactivity Influences Arm-Selective Activation of Pharmacological Endoplasmic Reticulum Proteostasis Regulators.bioRxiv : the preprint server for biology · 2023Article
- Normal tissue homeostasis and impairment of selective inflammatory responses in dendritic cells deficient for ATF6α.Frontiers in cell and developmental biology · 2023Article
- Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease.Frontiers in pharmacology · 2023Review
Corrections and comments
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Authors and funding
22 authors at 7 institutions in 3 countries.
Funding
Abstract
Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.
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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.