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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.<\/jats:p>","DOI":"10.1534\/genetics.119.302834","type":"journal-article","created":{"date-parts":[[2019,11,22]],"date-time":"2019-11-22T03:25:13Z","timestamp":1574393113000},"page":"121-134","source":"Crossref","is-referenced-by-count":28,"title":["Loss of Chondroitin Sulfate Modification Causes Inflammation and Neurodegeneration in <i>skt<\/i> Mice"],"prefix":"10.1093","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8324-506X","authenticated-orcid":false,"given":"Erica L","family":"Macke","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, University of Wisconsin-Madison, Wisconsin 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