ArticlePloS one2014
Ubiquilin-1 overexpression increases the lifespan and delays accumulation of Huntingtin aggregates in the R6/2 mouse model of Huntington's disease.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- Deubiquitinating enzymes at the crossroads of blood-brain barrier integrity and neurodegeneration: mechanistic insights, therapeutic targeting and future directions.Tissue barriers · 2026Review
- Pathophysiologic abnormalities in transgenic mice carrying the Alzheimer disease PSEN1 Δ440 mutation.Human molecular genetics · 2024Article
- Neurodegenerative Diseases: New Hopes and Perspectives.Current molecular medicine · 2024Review
- Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties.Nature communications · 2021Article
- Abnormally elevated ubiquilin‑1 expression in breast cancer regulates metastasis and stemness via AKT signaling.Oncology reports · 2021Article
- New Avenues for the Treatment of Huntington's Disease.International journal of molecular sciences · 2021Review
- Intracellular Sources of ROS/HCells · 2021Review
- Spatiotemporal analysis of soluble aggregates and autophagy markers in the R6/2 mouse model.Scientific reports · 2021Article
- Overexpression of UBQLN1 reduces neuropathology in the P497S UBQLN2 mouse model of ALS/FTD.Acta neuropathologica communications · 2020Article
- Ubiquilin-2 differentially regulates polyglutamine disease proteins.Human molecular genetics · 2020Article
- Therapeutic Advances for Huntington's Disease.Brain sciences · 2020Review
- Recognition and Degradation of Mislocalized Proteins in Health and Disease.Cold Spring Harbor perspectives in biology · 2019Review
- Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury.The Journal of clinical investigation · 2018Article
- Upregulation of PSMB8 and cathepsins in the human brains of dementia with Lewy bodies.Neuroscience letters · 2018Article
- New directions in therapeutics for Huntington disease.Future neurology · 2018Review
- Small molecule modulator of protein disulfide isomerase attenuates mutant huntingtin toxicity and inhibits endoplasmic reticulum stress in a mouse model of Huntington's disease.Human molecular genetics · 2018Article
- The Ubiquitin Receptor ADRM1 Modulates HAP40-Induced Proteasome Activity.Molecular neurobiology · 2017Article
- Proteostasis of Huntingtin in Health and Disease.International journal of molecular sciences · 2017Review
- Reduced body weight gain in ubiquilin-1 transgenic mice is associated with increased expression of energy-sensing proteins.Physiological reports · 2017Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Huntington's Disease (HD) is a neurodegenerative disorder that is caused by abnormal expansion of a polyglutamine tract in huntingtin (htt) protein. The expansion leads to increased htt aggregation and toxicity. Factors that aid in the clearance of mutant huntingtin proteins should relieve the toxicity. We previously demonstrated that overexpression of ubiqulin-1, which facilitates protein clearance through the proteasome and autophagy pathways, reduces huntingtin aggregates and toxicity in mammalian cell and invertebrate models of HD. Here we tested whether overexpression of ubiquilin-1 delays or prevents neurodegeneration in R6/2 mice, a well-established model of HD. We generated transgenic mice overexpressing human ubiquilin-1 driven by the neuron-specific Thy1.2 promoter. Immunoblotting and immunohistochemistry revealed robust and widespread overexpression of ubiquilin-1 in the brains of the transgenic mice. Similar analysis of R6/2 animals revealed that ubiquilin is localized in huntingtin aggregates and that ubiquilin levels decrease progressively to 30% during the end-stage of disease. We crossed our ubiquilin-1 transgenic line with R6/2 mice to assess whether restoration of ubiquilin levels would delay HD symptoms and pathology. In the double transgenic progeny, ubiquilin levels were fully restored, and this correlated with a 20% increase in lifespan and a reduction in htt inclusions in the hippocampus and cortex. Furthermore, immunoblots indicated that endoplasmic reticulum stress response that is elevated in the hippocampus of R6/2 animals was attenuated by ubiquilin-1 overexpression. However, ubiquilin-1 overexpression neither altered the load of htt aggregates in the striatum nor improved motor impairments in the mice.
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