title: Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling.
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.
authors.affiliation: Center for Molecular Biology and Genetics of Neurodegeneration, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Jindong
authors.initials: J
authors.lastname: Xu
authors.forename: Maria
authors.initials: M
authors.lastname: Xilouri
authors.forename: Julien
authors.initials: J
authors.lastname: Bruban
authors.forename: Junichi
authors.initials: J
authors.lastname: Shioi
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Shao
authors.forename: Ioannis
authors.initials: I
authors.lastname: Papazoglou
authors.forename: Kostas
authors.initials: K
authors.lastname: Vekrellis
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000077153:Progranulins; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D000077153:Progranulins; D018698:Glutamic Acid; D015655:1-Methyl-4-phenylpyridinium