ArticleHuman molecular genetics2016
NEDD4-mediated HSF1 degradation underlies α-synucleinopathy.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 93 citations in OpenAlex.
- Optimization of the recombinant overexpression and purification of human Nedd4-1 in Escherichia coli.Protein expression and purification · 2027Article
- From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.Metabolic brain disease · 2026Review
- Heat shock transcription factors in development and disease.Disease models & mechanisms · 2026Review
- Adaptive inter-tissue proteostasis networks in aging and neurodegeneration.Bioscience reports · 2026Review
- EP300 confers protection against acute pancreatitis via acetylating HSF1 and promoting PRKN-mediated mitophagy in pancreatic acinar cells.Cell communication and signaling : CCS · 2025Article
- HSF1-DBC1 axis drives prostate cancer progression by activating a metastatic transcriptional program.Experimental & molecular medicine · 2025Article
- Silica Nanoparticles Induced Epithelial-Mesenchymal Transition in BEAS-2B Cells via ER Stress and SIRT1/HSF1/HSPs Signaling Pathway.Journal of xenobiotics · 2025Article
- HSF1 Activation Mechanisms, Disease Roles, and Small Molecule Therapeutics.International journal of biological sciences · 2025Review
- The mechanosensitive geneAmerican journal of physiology. Cell physiology · 2024Article
- The ubiquitin codes in cellular stress responses.Protein & cell · 2024Review
- NEDD4-2 and the CLC-2 channel regulate neuronal excitability in the pathogenesis of mesial temporal lobe epilepsy.Scientific reports · 2024Article
- Disrupted HSF1 regulation in normal and exceptional brain aging.Biogerontology · 2024Article
- NADInternational journal of molecular sciences · 2024Article
- Melatonin derivative 6a as a PARP-1 inhibitor for the treatment of Parkinson's disease.Frontiers in pharmacology · 2024Article
- Polyphenols in Inner Ear Neurobiology, Health and Disease: From Bench to Clinics.Medicina (Kaunas, Lithuania) · 2023Review
- Proteostasis networks in aging: novel insights from text-mining approaches.Biogerontology · 2023Article
- Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons.The Journal of clinical investigation · 2023Article
- Heat shock factor HSF1 regulates BDNF gene promoters upon acute stress in the hippocampus, together with pCREB.Journal of neurochemistry · 2023Article
- Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington's disease.Cell reports · 2023Article
- The effect of progressive endurance training and extract of black winter truffle on proteins levels and expression of hippocampus α-synuclein and HSF1 in the healthy and diabetic rats.Metabolism open · 2023Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Cellular protein homeostasis is achieved by a delicate network of molecular chaperones and various proteolytic processes such as ubiquitin-proteasome system (UPS) to avoid a build-up of misfolded protein aggregates. The latter is a common denominator of neurodegeneration. Neurons are found to be particularly vulnerable to toxic stress from aggregation-prone proteins such as α-synuclein. Induction of heat-shock proteins (HSPs), such as through activated heat shock transcription factor 1 (HSF1) via Hsp90 inhibition, is being investigated as a therapeutic option for proteinopathic diseases. HSF1 is a master stress-protective transcription factor which activates genes encoding protein chaperones (e.g. iHsp70) and anti-apoptotic proteins. However, whether and how HSF1 is dysregulated during neurodegeneration has not been studied. Here, we discover aberrant HSF1 degradation by aggregated α-synuclein (or α-synuclein-induced proteotoxic stress) in transfected neuroblastoma cells. HSF1 dysregulation via α-synuclein was confirmed by in vivo assessment of mouse and in situ studies of human specimens with α-synucleinopathy. We demonstrate that elevated NEDD4 is implicated as the responsible ubiquitin E3 ligase for HSF1 degradation through UPS. Furthermore, pharmacologically induced SIRT1-mediated deacetylation can attenuate aberrant NEDD4-mediated HSF1 degradation. Indeed, we define the acetylation status of the Lys 80 residue located in the DNA-binding domain of HSF1 as a critical factor in modulating HSF1 protein stability in addition to its previously identified role in the transcriptional activity. Together with the finding that preserving HSF1 can alleviate α-synuclein toxicity, this study strongly suggests that aberrant HSF1 degradation is a key neurodegenerative mechanism underlying α-synucleinopathy.
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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.