期刊
NEUROBIOLOGY OF AGING
卷 34, 期 11, 页码 2541-2547出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2013.04.022
关键词
Progranulin; Sortilin; Granulin E; Frontotemporal lobar degeneration; Zebrafish; Blocking antibody
资金
- Belgian Neuromuscular Disease Association (ABBM)
- Belgian Foundation for Alzheimer Research (SAO-FRMA)
- Research Foundation-Flanders (FWO-Vlaanderen)
- University of Leuven
- Belgian government (Interuniversity Attraction Poles) of the Belgian Federal Science Policy Office [P6/43]
- FWO-Vlaanderen
- Agency for Innovation by Science and Technology (IWT)
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
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. (C) 2013 Elsevier Inc. All rights reserved.
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