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.

中文翻译：

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硫酸软骨素修饰的缺失会导致 skt 小鼠炎症和神经变性。


衰老过程的一个主要方面是慢性、低度炎症的发生，这种炎症与年龄相关疾病高度相关。调节这些过程的分子机制尚未完全阐明。我们已经鉴定出一种自发突变小鼠系，小而卷尾（ skt ），其表现出加速衰老和与年龄相关的疾病表型，包括大脑和视网膜炎症增加、年龄依赖性视网膜异常增强，包括感光细胞变性、神经退行性变。海马体，寿命缩短。通过定位克隆，我们发现了硫酸软骨素合酶 1 ( Chsy1 ) 的缺失，该缺失导致了skt小鼠的这些表型。 CHSY1 是软骨素 N-乙酰半乳糖胺基转移酶家族的成员，在硫酸软骨素的生物合成中发挥着关键作用，硫酸软骨素是一种附着在核心蛋白上形成硫酸软骨素蛋白聚糖 (CSPG) 的糖胺聚糖 (GAG)。与此功能一致的是， Chsy1突变显着减少了视网膜和海马中的硫酸软骨素 GAG。此外， skt小鼠的骨髓和脾脏中的巨噬细胞和中性粒细胞群出现显着改变，表明 CHSY1 在这些免疫细胞类型的功能中发挥着重要作用。因此，我们的研究揭示了 CHSY1 对视网膜和海马体的先前未知的影响。 具体来说，CHSY1 对蛋白质的硫酸软骨素 (CS) 修饰对于骨髓系免疫细胞的正确调节和维持神经元组织的完整性至关重要，因为该基因的缺陷会导致炎症增加和与年龄相关的异常表型。相关疾病。