Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium.
Neurobiol Aging. 2013 Nov;34(11):2541-7. doi: 10.1016/j.neurobiolaging.2013.04.022. Epub 2013 May 24.
Progranulin (PGRN) is a growth factor involved in wound healing, inflammation, tumor growth, and neurodegeneration. Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN to the membrane receptor sortilin (SORT1) mediates the endocytosis of PGRN. SORT1-mediated uptake plays an important role in the regulation of extracellular PGRN levels. We studied the role of SORT1 in PGRN-mediated neuroprotection in vitro and in vivo. The survival-enhancing effect of PGRN seemed to be dependent on the granulin E (GRN E) domain. Pharmacologic inhibition of the GRN E-SORT1 interaction or deletion of the SORT1 binding site of GRN E did not abolish its neurotrophic function. In addition, the in vivo phenotype of PGRN knockdown in zebrafish embryos was not phenocopied by SORT1 knockdown. These results suggest that GRN E mediates the neurotrophic properties of PGRN and that binding to SORT1 is not required for this effect.
颗粒体蛋白前体 (PGRN) 是一种参与伤口愈合、炎症、肿瘤生长和神经退行性变的生长因子。编码 PGRN 的基因突变导致 PGRN 短缺，并引起家族性额颞叶痴呆。PGRN 发挥神经营养作用，PGRN 与膜受体分选蛋白 1（SORT1）的结合介导 PGRN 的内吞作用。SORT1 介导的摄取在调节细胞外 PGRN 水平方面发挥着重要作用。我们研究了 SORT1 在 PGRN 介导的体外和体内神经保护中的作用。PGRN 的生存增强作用似乎依赖于颗粒蛋白 E（GRN E）结构域。GRN E-SORT1 相互作用的药理学抑制或 GRN E 的 SORT1 结合位点的缺失并没有消除其神经营养功能。此外，斑马鱼胚胎中 PGRN 敲低的体内表型不能被 SORT1 敲低所模拟。这些结果表明，GRN E 介导 PGRN 的神经营养特性，并且与 SORT1 的结合对于这种作用不是必需的。
