TY - JOUR
T1 - Progranulin regulates neuronal outgrowth independent of Sortilin
AU - Gass, Jennifer
AU - Lee, Wing C.
AU - Cook, Casey
AU - Finch, Nicole
AU - Stetler, Caroline
AU - Jansen-West, Karen
AU - Lewis, Jada
AU - Link, Christopher D.
AU - Rademakers, Rosa
AU - Nykjær, Anders
AU - Petrucelli, Leonard
N1 - Funding Information:
This work was supported by Mayo Clinic Foundation (LP), National Institutes of Health/National Institute on Aging [5R01AG026251-04(LP)], National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS 063964–01 (LP), R01 NS077402 (LP)], R01 NS065782 (RR), Amyotrophic Lateral Sclerosis Association (LP) and Department of Defense [W81XWH-10-1-0512-1 and W81XWH-09-1-0315AL093108 (LP)].
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Frontotemporal lobar degeneration
KW - Neuronal outgrowth
KW - Neurotrophic factor
KW - Progranulin
KW - Sortilin
UR - http://www.scopus.com/inward/record.url?scp=84863602114&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863602114&partnerID=8YFLogxK
U2 - 10.1186/1750-1326-7-33
DO - 10.1186/1750-1326-7-33
M3 - Article
C2 - 22781549
AN - SCOPUS:84863602114
SN - 1750-1326
VL - 7
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 33
ER -