Progranulin regulates neuronal outgrowth independent of Sortilin

Jennifer Gass, Wing C. Lee, Casey Cook, Nicole Finch, Caroline Stetler, Karen Jansen-West, Jada Lewis, Christopher D. Link, Rosa V Rademakers, Anders Nykjær, Leonard Petrucelli

Research output: Contribution to journalArticle

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Abstract

Background: Progranulin (PGRN), a widely secreted growth factor, is involved in multiple biological functions, and mutations located within the PGRN gene (GRN) are a major cause of frontotemporal lobar degeneration with TDP-43-positive inclusions (FLTD-TDP). In light of recent reports suggesting PGRN functions as a protective neurotrophic factor and that sortilin (SORT1) is a neuronal receptor for PGRN, we used a Sort1-deficient (Sort1) murine primary hippocampal neuron model to investigate whether PGRNs neurotrophic effects are dependent on SORT1. We sought to elucidate this relationship to determine what role SORT1, as a regulator of PGRN levels, plays in modulating PGRNs neurotrophic effects. Results: As the first group to evaluate the effect of PGRN loss in Grn knockout primary neuronal cultures, we show neurite outgrowth and branching are significantly decreased in Grn neurons compared to wild-type (WT) neurons. More importantly, we also demonstrate that PGRN overexpression can rescue this phenotype. However, the recovery in outgrowth is not observed following treatment with recombinant PGRN harboring missense mutations p.C139R, p.P248L or p.R432C, indicating that these mutations adversely affect the neurotrophic properties of PGRN. In addition, we also present evidence that cleavage of full-length PGRN into granulin peptides is required for increased neuronal outgrowth, suggesting that the neurotrophic functions of PGRN are contained within certain granulins. To further characterize the mechanism by which PGRN impacts neuronal morphology, we assessed the involvement of SORT1. We demonstrate that PGRN induced-outgrowth occurs in the absence of SORT1 in Sort1 cultures. Conclusion: We demonstrate that loss of PGRN impairs proper neurite outgrowth and branching, and that exogenous PGRN alleviates this impairment. Furthermore, we determined that exogenous PGRN induces outgrowth independent of SORT1, suggesting another receptor(s) is involved in PGRN induced neuronal outgrowth.

Original languageEnglish (US)
Article number33
JournalMolecular Neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - 2012

Fingerprint

Neurons
Frontotemporal Lobar Degeneration
Mutation
Nerve Growth Factors
Missense Mutation
Intercellular Signaling Peptides and Proteins
Phenotype
Peptides
sortilin
Neuronal Outgrowth
Genes
granulin precursor protein
Protective Factors

Keywords

  • Frontotemporal lobar degeneration
  • Neuronal outgrowth
  • Neurotrophic factor
  • Progranulin
  • Sortilin

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Progranulin regulates neuronal outgrowth independent of Sortilin. / Gass, Jennifer; Lee, Wing C.; Cook, Casey; Finch, Nicole; Stetler, Caroline; Jansen-West, Karen; Lewis, Jada; Link, Christopher D.; Rademakers, Rosa V; Nykjær, Anders; Petrucelli, Leonard.

In: Molecular Neurodegeneration, Vol. 7, No. 1, 33, 2012.

Research output: Contribution to journalArticle

Gass, J, Lee, WC, Cook, C, Finch, N, Stetler, C, Jansen-West, K, Lewis, J, Link, CD, Rademakers, RV, Nykjær, A & Petrucelli, L 2012, 'Progranulin regulates neuronal outgrowth independent of Sortilin', Molecular Neurodegeneration, vol. 7, no. 1, 33. https://doi.org/10.1186/1750-1326-7-33
Gass, Jennifer ; Lee, Wing C. ; Cook, Casey ; Finch, Nicole ; Stetler, Caroline ; Jansen-West, Karen ; Lewis, Jada ; Link, Christopher D. ; Rademakers, Rosa V ; Nykjær, Anders ; Petrucelli, Leonard. / Progranulin regulates neuronal outgrowth independent of Sortilin. In: Molecular Neurodegeneration. 2012 ; Vol. 7, No. 1.
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AU - Cook, Casey

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AU - Stetler, Caroline

AU - Jansen-West, Karen

AU - Lewis, Jada

AU - Link, Christopher D.

AU - Rademakers, Rosa V

AU - Nykjær, Anders

AU - Petrucelli, Leonard

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