The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding

Neurobiol Aging. 2013 Nov;34(11):2541-7. doi: 10.1016/j.neurobiolaging.2013.04.022. Epub 2013 May 24.

Abstract

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.

Keywords: Blocking antibody; Frontotemporal lobar degeneration; Granulin E; Progranulin; Sortilin; Zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / immunology
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Animals, Newborn
  • Antibodies / pharmacology
  • Binding Sites / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cyclic S-Oxides / pharmacology
  • Embryo, Nonmammalian
  • Embryonic Development / drug effects
  • Embryonic Development / genetics
  • Endocytosis / drug effects
  • Enzyme Inhibitors / pharmacology
  • Immunoprecipitation
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • Morpholines / pharmacology
  • Motor Neurons / cytology
  • Motor Neurons / drug effects*
  • Nerve Growth Factors / metabolism
  • Nerve Growth Factors / pharmacology*
  • Neurites / drug effects
  • Progranulins
  • Protein Structure, Tertiary / physiology
  • Rats
  • Rats, Wistar
  • Thiazoles / pharmacology
  • Zebrafish

Substances

  • Adaptor Proteins, Vesicular Transport
  • Antibodies
  • Cyclic S-Oxides
  • Enzyme Inhibitors
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Morpholines
  • Nerve Growth Factors
  • Progranulins
  • SSR 69071
  • Thiazoles
  • morpholine
  • sortilin