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PMID: 21092856 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin.

Neuron ·Vol. 68 ·No. 4 ·2010-11-18 ·Pages 654-67

Hu F, Padukkavidana T, Vægter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM

Abstract

The most common inherited form of Frontotemporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation and exhibits TDP-43 plus ubiquitin aggregates. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to cortical neurons via its C terminus, and unbiased expression cloning identifies Sortilin (Sort1) as a binding site. Sort1⁻/⁻ neurons exhibit reduced PGRN binding. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury. Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/⁻ mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD-TDP pathophysiology.

MeSH Terms
Adaptor Proteins, Vesicular Transport/deficiency,genetics,physiology Animals COS Cells Cells, Cultured Chlorocebus aethiops Endocytosis/genetics,physiology Frontotemporal Dementia/genetics,metabolism,physiopathology Granulins HEK293 Cells Humans Intercellular Signaling Peptides and Proteins/biosynthesis,genetics,metabolism Mice Mice, Inbred C57BL Mice, Knockout Progranulins Protein Binding/genetics,physiology Rats
Chemicals
Adaptor Proteins, Vesicular Transport Granulins Grn protein, mouse Intercellular Signaling Peptides and Proteins Progranulins sortilin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Hu Fenghua
Department of Neurology, Yale University School of Medicine, New Haven, CT 06536, USA.
Padukkavidana Thihan
Vægter Christian B
Brady Owen A
Zheng Yanqiu
Mackenzie Ian R
Feldman Howard H
Nykjaer Anders
Strittmatter Stephen M
References (47)
47 references, click to expand
  1. A gene network regulating lysosomal biogenesis and function.
    Science. 2009 Jul 24;325(5939):473-7 PMID: 19556463
  2. Synergistic effect between proteasome and autophagosome in the clearance of polyubiquitinated TDP-43.
    J Neurosci Res. 2010 Mar;88(4):784-97 PMID: 19798749
  3. Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members.
    Biochem J. 2006 Apr 15;395(2):285-93 PMID: 16393139
  4. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.
    Science. 2008 Mar 21;319(5870):1668-72 PMID: 18309045
  5. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.
    Nat Genet. 2004 Apr;36(4):377-81 PMID: 15034582
  6. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.
    Hum Mol Genet. 2006 Oct 15;15(20):2988-3001 PMID: 16950801
  7. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration.
    Acta Neuropathol. 2007 Jul;114(1):5-22 PMID: 17579875
  8. Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system.
    Neurosci Lett. 2010 Jan 18;469(1):112-6 PMID: 19944744
  9. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations.
    Acta Neuropathol. 2009 Jan;117(1):15-8 PMID: 19015862
  10. Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury.
    Brain Res. 2009 Jan 16;1249:202-11 PMID: 19046946
  11. Progranulin is a mediator of the wound response.
    Nat Med. 2003 Feb;9(2):225-9 PMID: 12524533
  12. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury.
    Nat Neurosci. 2007 Nov;10(11):1449-57 PMID: 17934455
  13. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members.
    Brain. 2009 Mar;132(Pt 3):583-91 PMID: 19158106
  14. The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene.
    Brain. 2006 Nov;129(Pt 11):3081-90 PMID: 17071926
  15. The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes.
    Exp Cell Res. 2009 Nov 1;315(18):3112-24 PMID: 19732768
  16. Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone.
    Hum Mol Genet. 2010 May 1;19(9):1741-55 PMID: 20147319
  17. Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene.
    Behav Brain Res. 2007 Dec 28;185(2):110-8 PMID: 17764761
  18. Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging.
    Am J Pathol. 2010 Jul;177(1):311-24 PMID: 20522652
  19. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin.
    J Neurosci. 2005 Jun 1;25(22):5455-63 PMID: 15930396
  20. Nogo-A interacts with the Nogo-66 receptor through multiple sites to create an isoform-selective subnanomolar agonist.
    J Neurosci. 2005 Jun 1;25(22):5298-304 PMID: 15930377
  21. Sortilin is essential for proNGF-induced neuronal cell death.
    Nature. 2004 Feb 26;427(6977):843-8 PMID: 14985763
  22. Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration.
    Neurology. 2008 Oct 14;71(16):1235-9 PMID: 18768919
  23. Ligands bind to Sortilin in the tunnel of a ten-bladed beta-propeller domain.
    Nat Struct Mol Biol. 2009 Jan;16(1):96-8 PMID: 19122660
  24. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice.
    J Exp Med. 2010 Jan 18;207(1):117-28 PMID: 20026663
  25. Vps10p cycles between the late-Golgi and prevacuolar compartments in its function as the sorting receptor for multiple yeast vacuolar hydrolases.
    J Cell Biol. 1996 May;133(3):529-41 PMID: 8636229
  26. Axonal ligation induces transient redistribution of TDP-43 in brainstem motor neurons.
    Neuroscience. 2009 Dec 29;164(4):1565-78 PMID: 19782731
  27. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein.
    EMBO J. 2001 May 1;20(9):2180-90 PMID: 11331584
  28. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.
    Nat Genet. 2008 May;40(5):572-4 PMID: 18372902
  29. The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin.
    EMBO J. 2003 Dec 15;22(24):6430-7 PMID: 14657016
  30. Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability.
    J Biol Chem. 2009 Oct 2;284(40):27416-24 PMID: 19651785
  31. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.
    Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6 PMID: 16174740
  32. Sortilin, SorCS1b, and SorLA Vps10p sorting receptors, are novel gamma-secretase substrates.
    Mol Neurodegener. 2006 Jun 12;1:3 PMID: 16930450
  33. Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival.
    J Cell Biol. 2008 Apr 7;181(1):37-41 PMID: 18378771
  34. VPS10P-domain receptors - regulators of neuronal viability and function.
    Nat Rev Neurosci. 2008 Dec;9(12):899-909 PMID: 19002190
  35. Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair.
    Cell. 2002 Dec 13;111(6):867-78 PMID: 12526812
  36. Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.
    J Cell Biol. 2009 Dec 14;187(6):875-88 PMID: 20008565
  37. Pro-NGF secreted by astrocytes promotes motor neuron cell death.
    Mol Cell Neurosci. 2007 Feb;34(2):271-9 PMID: 17188890
  38. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration.
    Nature. 2001 Jan 18;409(6818):341-6 PMID: 11201742
  39. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.
    Nature. 2006 Aug 24;442(7105):916-9 PMID: 16862116
  40. The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and mannose 6-phosphate receptor.
    Traffic. 2006 Jul;7(7):889-902 PMID: 16787399
  41. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers.
    Nature. 2009 Feb 26;457(7233):1128-32 PMID: 19242475
  42. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.
    Nature. 2006 Aug 24;442(7105):920-4 PMID: 16862115
  43. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.
    Nat Genet. 2007 Feb;39(2):168-77 PMID: 17220890
  44. Serum biomarker for progranulin-associated frontotemporal lobar degeneration.
    Ann Neurol. 2009 May;65(5):603-9 PMID: 19288468
  45. Progranulin is expressed within motor neurons and promotes neuronal cell survival.
    BMC Neurosci. 2009 Oct 27;10:130 PMID: 19860916
  46. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
    Science. 2006 Oct 6;314(5796):130-3 PMID: 17023659
  47. Sortilin mediates the lysosomal targeting of cathepsins D and H.
    Biochem Biophys Res Commun. 2008 Aug 22;373(2):292-7 PMID: 18559255
Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2010.09.034
Published
2010-11-18
Pages
654-67
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC2990962
Subset
IM
Grants
NINDS NIH HHS · R01 NS042304-09 · United States
NINDS NIH HHS · R37 NS033020-19 · United States
NIDA NIH HHS · P30 DA018343 · United States
NINDS NIH HHS · R01 NS042304 · United States
NIA NIH HHS · R01 AG034924 · United States
NINDS NIH HHS · R01 NS039962 · United States
NINDS NIH HHS · R01 NS039962-11 · United States
NIA NIH HHS · R01 AG034924-01A1 · United States
CIHR · Canada
NINDS NIH HHS · R37 NS033020 · United States
Corrections
CommentIn
PMID: 21092851
External Links
PubMed source DOI: 10.1016/j.neuron.2010.09.034 PMC Full Text View journal details
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