Format

Send to

Choose Destination
Genetics. 2020 Jan;214(1):121-134. doi: 10.1534/genetics.119.302834. Epub 2019 Nov 21.

Loss of Chondroitin Sulfate Modification Causes Inflammation and Neurodegeneration in skt Mice.

Author information

1
Department of Medical Genetics, University of Wisconsin-Madison, Wisconsin 53706.
2
Department of Biochemistry, University of Wisconsin-Madison, Wisconsin 53706.
3
Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Wisconsin 53706.
4
Institute for Molecular Virology, University of Wisconsin-Madison, Wisconsin 53706.
5
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin 53706.
6
Department of Pediatrics, University of Wisconsin-Madison, Wisconsin 53706.
7
Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Wisconsin 53706.
8
McPherson Eye Research Institute, University of Wisconsin-Madison, Wisconsin 53706.
9
Department of Medical Genetics, University of Wisconsin-Madison, Wisconsin 53706 aikeda@wisc.edu.

Abstract

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.

KEYWORDS:

aging; chondroitin sulfate synthase; hippocampus; inflammation; mouse; myeloid cells; neurodegeneration; retina; retinal pigment epithelium; subretinal space

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center