PDF(Pubmed)
Abstract：
The naked mole rat (NMR) is the longest-lived rodent, resistant to multiple age-related diseases including neurodegeneration. However, the mechanisms underlying the NMR\'s resistance to neurodegenerative diseases remain elusive. Here, we isolated oligodendrocyte progenitor cells (OPCs) from NMRs and compared their transcriptome with that of other mammals. Extracellular matrix (ECM) genes best distinguish OPCs of long- and short-lived species. Notably, expression levels of CD44, an ECM-binding protein that has been suggested to contribute to NMR longevity by mediating the effect of hyaluronan (HA), are not only high in OPCs of long-lived species but also positively correlate with longevity in multiple cell types/tissues. We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA. HA-independent role of CD44 in proteostasis regulation may contribute to mammalian longevity.
摘要：
裸mole鼠（NMR）是寿命最长的啮齿动物，抵抗多种年龄相关疾病，包括神经变性。然而,核磁共振对神经退行性疾病的抵抗机制仍然难以捉摸。这里,我们从NMR中分离出少突胶质祖细胞（OPCs），并将其转录组与其他哺乳动物的转录组进行比较。细胞外基质（ECM）基因最能区分长命和短命物种的OPCs。值得注意的是,CD44的表达水平，这是一种ECM结合蛋白，被认为通过介导透明质酸（HA）的作用来促进NMR寿命，不仅在长寿命物种的OPCs中含量高，而且与多种细胞类型/组织的寿命呈正相关。我们发现CD44定位于内质网（ER）并增强基础ATF6活性。CD44修饰ER的蛋白质组和膜特性，并以依赖于未折叠蛋白质反应调节剂而不需要HA的方式增强ER应激抗性。CD44在蛋白质停滞调节中的HA非依赖性作用可能有助于哺乳动物的长寿。
