FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2085095087> ?p ?o ?g. }

• W2085095087 endingPage "13925" @default.
• W2085095087 startingPage "13912" @default.
• W2085095087 abstract "Loss of Ostm1 leads to the most severe form of osteopetrosis in mice and humans. Because functional rescue of the osteopetrotic defect in these mice extended their lifespan from ∼3 weeks to 6 weeks, this unraveled a second essential role of Ostm1. We discovered that Ostm1 is highly expressed in the mouse brain in neurons, microglia, and astrocytes. At 3–4 weeks of age, mice with Ostm1 loss showed 3–10-fold stimulation of reactive gliosis, with an increased astrocyte cell population and microglia activation. This inflammatory response was associated with marked retinal photoreceptor degeneration and massive neuronal loss in the brain. Intracellular characterization of neurons revealed abnormal storage of carbohydrates, lipids, and ubiquitinated proteins, combined with marked accumulation of autophagosomes that causes frequent axonal swelling. Stimulation of autophagy was provided by specific markers and by significant down-regulation of the mammalian target of rapamycin signaling, identifying a cellular pathologic mechanism. A series of transgenic mouse lines specifically targeted to distinct central nervous system cell subpopulations determined that Ostm1 has a primary and autonomous role in neuronal homeostasis. Complete functional complementation demonstrated that the development of severe and rapid neurodegeneration in these mice is independent of the hematopoietic lineage and has clinical implications for treatment of osteopetrosis. Importantly, this study establishes a novel neurodegenerative mouse model critical for understanding the multistep pathogenic cascade of cellular autophagy disorders toward therapeutic strategy design. Loss of Ostm1 leads to the most severe form of osteopetrosis in mice and humans. Because functional rescue of the osteopetrotic defect in these mice extended their lifespan from ∼3 weeks to 6 weeks, this unraveled a second essential role of Ostm1. We discovered that Ostm1 is highly expressed in the mouse brain in neurons, microglia, and astrocytes. At 3–4 weeks of age, mice with Ostm1 loss showed 3–10-fold stimulation of reactive gliosis, with an increased astrocyte cell population and microglia activation. This inflammatory response was associated with marked retinal photoreceptor degeneration and massive neuronal loss in the brain. Intracellular characterization of neurons revealed abnormal storage of carbohydrates, lipids, and ubiquitinated proteins, combined with marked accumulation of autophagosomes that causes frequent axonal swelling. Stimulation of autophagy was provided by specific markers and by significant down-regulation of the mammalian target of rapamycin signaling, identifying a cellular pathologic mechanism. A series of transgenic mouse lines specifically targeted to distinct central nervous system cell subpopulations determined that Ostm1 has a primary and autonomous role in neuronal homeostasis. Complete functional complementation demonstrated that the development of severe and rapid neurodegeneration in these mice is independent of the hematopoietic lineage and has clinical implications for treatment of osteopetrosis. Importantly, this study establishes a novel neurodegenerative mouse model critical for understanding the multistep pathogenic cascade of cellular autophagy disorders toward therapeutic strategy design." @default.
• W2085095087 created "2016-06-24" @default.
• W2085095087 creator A5000486634 @default.
• W2085095087 creator A5006773025 @default.
• W2085095087 creator A5015278586 @default.
• W2085095087 creator A5026043721 @default.
• W2085095087 creator A5063664912 @default.
• W2085095087 creator A5070853048 @default.
• W2085095087 date "2014-05-01" @default.
• W2085095087 modified "2023-10-17" @default.
• W2085095087 title "Severe Neurodegeneration with Impaired Autophagy Mechanism Triggered by Ostm1 Deficiency" @default.
• W2085095087 cites W1900339045 @default.
• W2085095087 cites W1904875888 @default.
• W2085095087 cites W1966773767 @default.
• W2085095087 cites W1977649097 @default.
• W2085095087 cites W1983037161 @default.
• W2085095087 cites W1994834331 @default.
• W2085095087 cites W1995645788 @default.
• W2085095087 cites W2004864232 @default.
• W2085095087 cites W2005144914 @default.
• W2085095087 cites W2006524711 @default.
• W2085095087 cites W2006582030 @default.
• W2085095087 cites W2009517899 @default.
• W2085095087 cites W2019270801 @default.
• W2085095087 cites W2022812113 @default.
• W2085095087 cites W2032499946 @default.
• W2085095087 cites W2033113948 @default.
• W2085095087 cites W2041455826 @default.
• W2085095087 cites W2043291430 @default.
• W2085095087 cites W2043642541 @default.
• W2085095087 cites W2057728518 @default.
• W2085095087 cites W2068147651 @default.
• W2085095087 cites W2074367129 @default.
• W2085095087 cites W2082306524 @default.
• W2085095087 cites W2082732734 @default.
• W2085095087 cites W2088894092 @default.
• W2085095087 cites W2093637710 @default.
• W2085095087 cites W2097631517 @default.
• W2085095087 cites W2102661252 @default.
• W2085095087 cites W2103104037 @default.
• W2085095087 cites W2103307128 @default.
• W2085095087 cites W2103377481 @default.
• W2085095087 cites W2108086395 @default.
• W2085095087 cites W2109034822 @default.
• W2085095087 cites W2111567059 @default.
• W2085095087 cites W2122318491 @default.
• W2085095087 cites W2122508074 @default.
• W2085095087 cites W2128537698 @default.
• W2085095087 cites W2129023888 @default.
• W2085095087 cites W2138132767 @default.
• W2085095087 cites W2144219438 @default.
• W2085095087 cites W2148898943 @default.
• W2085095087 cites W2161234475 @default.
• W2085095087 cites W2162362319 @default.
• W2085095087 cites W2166911293 @default.
• W2085095087 cites W2597260089 @default.
• W2085095087 doi "https://doi.org/10.1074/jbc.m113.537233" @default.
• W2085095087 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4022863" @default.
• W2085095087 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24719316" @default.
• W2085095087 hasPublicationYear "2014" @default.
• W2085095087 type Work @default.
• W2085095087 sameAs 2085095087 @default.
• W2085095087 citedByCount "27" @default.
• W2085095087 countsByYear W20850950872014 @default.
• W2085095087 countsByYear W20850950872015 @default.
• W2085095087 countsByYear W20850950872016 @default.
• W2085095087 countsByYear W20850950872017 @default.
• W2085095087 countsByYear W20850950872018 @default.
• W2085095087 countsByYear W20850950872020 @default.
• W2085095087 countsByYear W20850950872021 @default.
• W2085095087 countsByYear W20850950872022 @default.
• W2085095087 crossrefType "journal-article" @default.
• W2085095087 hasAuthorship W2085095087A5000486634 @default.
• W2085095087 hasAuthorship W2085095087A5006773025 @default.
• W2085095087 hasAuthorship W2085095087A5015278586 @default.
• W2085095087 hasAuthorship W2085095087A5026043721 @default.
• W2085095087 hasAuthorship W2085095087A5063664912 @default.
• W2085095087 hasAuthorship W2085095087A5070853048 @default.
• W2085095087 hasBestOaLocation W20850950871 @default.
• W2085095087 hasConcept C102230213 @default.
• W2085095087 hasConcept C104317684 @default.
• W2085095087 hasConcept C141035611 @default.
• W2085095087 hasConcept C142724271 @default.
• W2085095087 hasConcept C169760540 @default.
• W2085095087 hasConcept C190283241 @default.
• W2085095087 hasConcept C203014093 @default.
• W2085095087 hasConcept C203522944 @default.
• W2085095087 hasConcept C2776914184 @default.
• W2085095087 hasConcept C2776925932 @default.
• W2085095087 hasConcept C2777542381 @default.
• W2085095087 hasConcept C2777682930 @default.
• W2085095087 hasConcept C2779134260 @default.
• W2085095087 hasConcept C2779830541 @default.
• W2085095087 hasConcept C2781078528 @default.
• W2085095087 hasConcept C529278444 @default.
• W2085095087 hasConcept C54355233 @default.
• W2085095087 hasConcept C71924100 @default.
• W2085095087 hasConcept C86803240 @default.

• next