Progranulin regulates neuronal outgrowth independent of Sortilin
10.1186/1750-1326-7-33
Crossref journal-article
Springer Science and Business Media LLC
Molecular Neurodegeneration (297)
Abstract

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 PGRN’s 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 PGRN’s 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.

Bibliography

Gass, J., Lee, W. C., Cook, C., Finch, N., Stetler, C., Jansen-West, K., Lewis, J., Link, C. D., Rademakers, R., Nykjær, A., & Petrucelli, L. (2012). Progranulin regulates neuronal outgrowth independent of Sortilin. Molecular Neurodegeneration, 7(1).

Authors 11
  1. Jennifer Gass (first)
  2. Wing C Lee (additional)
  3. Casey Cook (additional)
  4. Nicole Finch (additional)
  5. Caroline Stetler (additional)
  6. Karen Jansen-West (additional)
  7. Jada Lewis (additional)
  8. Christopher D Link (additional)
  9. Rosa Rademakers (additional)
  10. Anders Nykjær (additional)
  11. Leonard Petrucelli (additional)
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Dates
Type When
Created 13 years, 1 month ago (July 10, 2012, 4:58 p.m.)
Deposited 3 years, 11 months ago (Sept. 3, 2021, 6:25 p.m.)
Indexed 3 weeks, 6 days ago (July 30, 2025, 10:30 a.m.)
Issued 13 years, 1 month ago (July 10, 2012)
Published 13 years, 1 month ago (July 10, 2012)
Published Online 13 years, 1 month ago (July 10, 2012)
Published Print 12 years, 8 months ago (Dec. 1, 2012)
Funders 0

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@article{Gass_2012, title={Progranulin regulates neuronal outgrowth independent of Sortilin}, volume={7}, ISSN={1750-1326}, url={http://dx.doi.org/10.1186/1750-1326-7-33}, DOI={10.1186/1750-1326-7-33}, number={1}, journal={Molecular Neurodegeneration}, publisher={Springer Science and Business Media LLC}, author={Gass, Jennifer and Lee, Wing C and Cook, Casey and Finch, Nicole and Stetler, Caroline and Jansen-West, Karen and Lewis, Jada and Link, Christopher D and Rademakers, Rosa and Nykjær, Anders and Petrucelli, Leonard}, year={2012}, month=jul }