Loss of Chondroitin Sulfate Modification Causes Inflammation and Neurodegeneration in skt Mice
| Autor: | Nicholas A. Zumwalde, Erik Jessen, Daniel Western, Erika Henningsen, Anna-Lisa Doebley, Akihiro Ikeda, Michael Landowski, Samuel A. Miller, Sakae Ikeda, Nathan P Gruenke, Erica L. Macke, Bikash R. Pattnaik, Jenny E. Gumperz, Wei-Hua Lee, Che Liu |
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| Rok vydání: | 2020 |
| Předmět: |
Male
retina hippocampus retinal pigment epithelium Apoptosis Mice chemistry.chemical_compound 0302 clinical medicine Chondroitin sulfate synthase 1 subretinal space Glucuronosyltransferase Mice Knockout Neurons Genetics 0303 health sciences Chondroitin Sulfates Retinal Degeneration Neurodegeneration Age Factors neurodegeneration Neurodegenerative Diseases Cell biology medicine.anatomical_structure myeloid cells N-Acetylgalactosaminyltransferases Female medicine.symptom Positional cloning Inflammation Investigations Biology 03 medical and health sciences Cellular Genetics medicine Animals Chondroitin Chondroitin sulfate mouse 030304 developmental biology Retinal pigment epithelium aging Proteins medicine.disease Multifunctional Enzymes Mice Inbred C57BL chemistry chondroitin sulfate synthase Chondroitin sulfate proteoglycan Mutation Protein Processing Post-Translational 030217 neurology & neurosurgery |
| Zdroj: | Genetics |
| ISSN: | 1943-2631 |
| DOI: | 10.1534/genetics.119.302834 |
| Popis: | One major aspect of the aging process is the onset of chronic, low-grade inflammation that is highly associated with age-related diseases. The molecular mechanisms that regulate these processes have not been fully elucidated. We have identified a spontaneous mutant mouse line, small with kinky tail (skt), that exhibits accelerated aging and age-related disease phenotypes including increased inflammation in the brain and retina, enhanced age-dependent retinal abnormalities including photoreceptor cell degeneration, neurodegeneration in the hippocampus, and reduced lifespan. By positional cloning, we identified a deletion in chondroitin sulfate synthase 1 (Chsy1) that is responsible for these phenotypes in skt mice. CHSY1 is a member of the chondroitin N-acetylgalactosaminyltransferase family that plays critical roles in the biosynthesis of chondroitin sulfate, a glycosaminoglycan (GAG) that is attached to the core protein to form the chondroitin sulfate proteoglycan (CSPG). Consistent with this function, the Chsy1 mutation dramatically decreases chondroitin sulfate GAGs in the retina and hippocampus. In addition, macrophage and neutrophil populations appear significantly altered in the bone marrow and spleen of skt mice, suggesting an important role for CHSY1 in the functioning of these immune cell types. Thus, our study reveals a previously unidentified impact of CHSY1 in the retina and hippocampus. Specifically, chondroitin sulfate (CS) modification of proteins by CHSY1 appears critical for proper regulation of immune cells of the myeloid lineage and for maintaining the integrity of neuronal tissues, since a defect in this gene results in increased inflammation and abnormal phenotypes associated with age-related diseases. |
| Databáze: | OpenAIRE |
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