Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling

• Published in: Neurobiology of aging Vol. 32; no. 12; pp. 2326.e5 - 2326.e16
• Main Authors: Xu, Jindong, Xilouri, Maria, Bruban, Julien, Shioi, Junichi, Shao, Zhiping, Papazoglou, Ioannis, Vekrellis, Kostas, Robakis, Nikolaos K
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2011
• Subjects: 1-Methyl-4-phenylpyridinium - toxicity; Akt; Animals; Cell Survival - physiology; Cells, Cultured; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - physiology; ERK; Excitotoxicity; Extracellular Fluid - drug effects; Extracellular Fluid - metabolism; Extracellular Space - drug effects; Extracellular Space - physiology; Frontotemporal lobar degeneration; Glutamic Acid - toxicity; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins - physiology; Internal Medicine; Neurodegeneration; Neurology; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - pharmacology; Oxidative stress; Progranulin; Rats; Rats, Wistar; Signal Transduction - drug effects; Signal Transduction - physiology; Neuroprotection; Oxidative stress; extracellular signal-regulated kinase; TAR; MPP; MTT; BSA; DMEM; LDH; Neurodegeneration; FBS; PCDGF; ethylenediaminetetraacetic acid; polyacrylamide gel electrophoresis; sodium dodecyl sulfate; brain-derived neurotrophic factor; trans-activation response element; PBS; methylthiazolyldiphenyl-tetrazolium bromide; Progranulin; SDS; BDNF; pheochromocytoma; S6 kinase; lactate dehydrogenase; Frontotemporal lobar degeneration; PAGE; phosphate buffer saline; Akt; MAPK/ERK kinases; phosphorylated; EDTA; Dulbecco's modified Eagle's medium; 1-methyl-4-phenylpyridinium; p; fetal bovine serum; MEK; PC; Excitotoxicity; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP; bovine serum albumin; ERK
• DOI: 10.1016/j.neurobiolaging.2011.06.017
• ISSN: 0197-4580

Abstract To reduce damage from toxic insults such as glutamate excitotoxicity and oxidative stresses, neurons may deploy an array of neuroprotective mechanisms. Recent reports show that progranulin ( PGRN ) gene null or missense mutations leading to inactive protein, are linked to frontotemporal lobar degeneration (FTLD), suggesting that survival of certain neuronal populations needs full expression of functional PGRN. Here we show that extracellular PGRN stimulates phosphorylation/activation of the neuronal MEK/extracellular regulated kinase (ERK)/p90 ribosomal S6 kinase (p90RSK) and phosphatidylinositol-3 kinase (PI3K)/Akt cell survival pathways and rescues cortical neurons from cell death induced by glutamate or oxidative stress. Pharmacological inhibition of MEK/ERK/p90RSK signaling blocks the PGRN-induced phosphorylation and neuroprotection against glutamate toxicity while inhibition of either MEK/ERK/p90RSK or PI3K/Akt blocks PGRN protection against neurotoxin MPP+ . Inhibition of both pathways had synergistic effects on PGRN-dependent neuroprotection against MPP+ toxicity suggesting both pathways contribute to the neuroprotective activities of PGRN. Extracellular PGRN is remarkably stable in neuronal cultures indicating neuroprotective activities are associated with full-length protein. Together, our data show that extracellular PGRN acts as a neuroprotective factor and support the hypothesis that in FTLD reduction of functional brain PGRN results in reduced survival signaling and decreased neuronal protection against excitotoxicity and oxidative stress leading to accelerated neuronal cell death. That extracellular PGRN has neuroprotective functions against toxic insults suggests that in vitro preparations of this protein may be used therapeutically.