ArticleActa neuropathologica2012
Long-term proteasomal inhibition in transgenic mice by UBB(+1) expression results in dysfunction of central respiration control reminiscent of brainstem neuropathology in Alzheimer patients.
Article in Acta neuropathologica, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 33 citations in OpenAlex.
- Multiomic Analyses Reveal Brainstem Metabolic Changes in a Mouse Model of Dravet Syndrome.Cells · 2025Article
- Molecular mechanisms underlying p62-dependent secretion of the Alzheimer-associated ubiquitin variant UBBProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Gene Expression Signatures of Immaturity, Decreased pH, and Neural Hyperexcitation in the Hippocampus of Alzheimer's Disease Model Mice.Neuropsychopharmacology reports · 2025Article
- Altered ubiquitin signaling induces Alzheimer's disease-like hallmarks in a three-dimensional human neural cell culture model.Nature communications · 2023Article
- Transgenic rodents as dynamic models for the study of respiratory rhythm generation and modulation: a scoping review and a bibliometric analysis.Frontiers in physiology · 2023Article
- USP10 deubiquitinates Tau, mediating its aggregation.Cell death & disease · 2022Article
- The Dose-Dependent Pleiotropic Effects of the UBBFrontiers in molecular biosciences · 2021Review
- A Systematic Bioinformatics Workflow With Meta-Analytics Identified Potential Pathogenic Factors of Alzheimer's Disease.Frontiers in neuroscience · 2020Article
- Mutant ubiquitin reduces Aβ plaques.Aging · 2018Article
- Dysfunction of Protein Quality Control in Parkinsonism-Dementia Complex of Guam.Frontiers in neurology · 2018Article
- Deposition of mutant ubiquitin in parkinsonism-dementia complex of Guam.Acta neuropathologica communications · 2017Article
- Selective Transgenic Expression of Mutant Ubiquitin in Purkinje Cell Stripes in the Cerebellum.Cerebellum (London, England) · 2017Article
- Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo.Acta neuropathologica · 2017Article
- Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls.Aging cell · 2016Article
- The fine-tuning of proteolytic pathways in Alzheimer's disease.Cellular and molecular life sciences : CMLS · 2016Review
- The Ubiquitin-Proteasome System: Potential Therapeutic Targets for Alzheimer's Disease and Spinal Cord Injury.Frontiers in molecular neuroscience · 2016Review
- Ubiquitin-dependent proteolysis in yeast cells expressing neurotoxic proteins.Frontiers in molecular neuroscience · 2015Review
- Misframed ubiquitin and impaired protein quality control: an early event in Alzheimer's disease.Frontiers in molecular neuroscience · 2015Review
- Localization of mutant ubiquitin in the brain of a transgenic mouse line with proteasomal inhibition and its validation at specific sites in Alzheimer's disease.Frontiers in neuroanatomy · 2015Article
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19 authors at 5 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases, a mutant form of ubiquitin B (UBB(+1)) accumulates in disease-specific aggregates. UBB(+1) mRNA is generated at low levels in vivo during transcription from the ubiquitin B locus by molecular misreading. The resulting mutant protein has been shown to inhibit proteasome function. To elucidate causative effects and neuropathological consequences of UBB(+1) accumulation, we used a UBB(+1) expressing transgenic mouse line that models UPS inhibition in neurons and exhibits behavioral phenotypes reminiscent of Alzheimer's disease (AD). In order to reveal affected organs and functions, young and aged UBB(+1) transgenic mice were comprehensively phenotyped for more than 240 parameters. This revealed unexpected changes in spontaneous breathing patterns and an altered response to hypoxic conditions. Our findings point to a central dysfunction of respiratory regulation in transgenic mice in comparison to wild-type littermate mice. Accordingly, UBB(+1) was strongly expressed in brainstem regions of transgenic mice controlling respiration. These regions included, e.g., the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nucleus. In addition, UBB(+1) was also strongly expressed in these anatomical structures of AD patients (Braak stage #6) and was not expressed in non-demented controls. We conclude that long-term UPS inhibition due to UBB(+1) expression causes central breathing dysfunction in a transgenic mouse model of AD. The UBB(+1) expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients.
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