title: Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds.
abstract: Recent experimental evidence suggests that transcellular propagation of fibrillar protein aggregates drives the progression of neurodegenerative diseases in a prion-like manner. This phenomenon is now well described in cell and animal models and involves the release of protein aggregates into the extracellular space. Free aggregates then enter neighboring cells to seed further fibrillization. The mechanism by which aggregated extracellular proteins such as tau and α-synuclein bind and enter cells to trigger intracellular fibril formation is unknown. Prior work indicates that prion protein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface to transmit pathologic processes. Here, we find that tau fibril uptake also occurs via HSPG binding. This is blocked in cultured cells and primary neurons by heparin, chlorate, heparinase, and genetic knockdown of a key HSPG synthetic enzyme, Ext1. Interference with tau binding to HSPGs prevents recombinant tau fibrils from inducing intracellular aggregation and blocks transcellular aggregate propagation. In vivo, a heparin mimetic, F6, blocks neuronal uptake of stereotactically injected tau fibrils. Finally, uptake and seeding by α-synuclein fibrils, but not huntingtin fibrils, occurs by the same mechanism as tau. This work suggests a unifying mechanism of cell uptake and propagation for tauopathy and synucleinopathy.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Brandon B
authors.initials: BB
authors.lastname: Holmes
authors.forename: Sarah L
authors.initials: SL
authors.lastname: DeVos
authors.forename: Najla
authors.initials: N
authors.lastname: Kfoury
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Rachel
authors.initials: R
authors.lastname: Jacks
authors.forename: Kiran
authors.initials: K
authors.lastname: Yanamandra
authors.forename: Mohand O
authors.initials: MO
authors.lastname: Ouidja
authors.forename: Frances M
authors.initials: FM
authors.lastname: Brodsky
authors.forename: Jayne
authors.initials: J
authors.lastname: Marasa
authors.forename: Devika P
authors.initials: DP
authors.lastname: Bagchi
authors.forename: Paul T
authors.initials: PT
authors.lastname: Kotzbauer
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
authors.forename: Dulce
authors.initials: D
authors.lastname: Papy-Garcia
authors.forename: Marc I
authors.initials: MI
authors.lastname: Diamond
mesh_terms: D000199:Actins / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D058953:Neural Stem Cells / Q000378:metabolism* / Q000502:physiology; D010873:Pinocytosis / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D000682:Amyloid; D019812:Heparan Sulfate Proteoglycans; D007211:Indoles; C558298:Mapt protein, mouse; D016875:tau Proteins; C007293:DAPI
keywords: Alzheimer's disease; macropinocytosis; neurodegeneration; prion-like mechanisms
references.citation: Acta Neuropathol. 1991;82(4):239-59
references.pmid: 1759558
references.citation: J Virol. 2002 Oct;76(19):9920-33
references.pmid: 12208969
references.citation: Biochem J. 2010 May 27;428(3):463-71
references.pmid: 20377530
references.citation: J Am Chem Soc. 2011 Jan 19;133(2):334-44
references.pmid: 21142149
references.citation: Neurobiol Aging. 1997 Jul-Aug;18(4 Suppl):S85-8
references.pmid: 9330992
references.citation: Biochem Biophys Res Commun. 2003 Dec 12;312(2):473-9
references.pmid: 14637161
references.citation: J Clin Invest. 2011 Feb;121(2):715-25
references.pmid: 21245577
references.citation: Biochemistry. 1986 Apr 22;25(8):2231-7
references.pmid: 3754765
references.citation: J Biol Chem. 1997 Dec 12;272(50):31617-24
references.pmid: 9395501
references.citation: PLoS One. 2008;3(10):e3314
references.pmid: 19390657
references.citation: J Biol Chem. 2003 Sep 12;278(37):35109-14
references.pmid: 12837762
references.citation: Neuron. 2012 Mar 22;73(6):1216-27
references.pmid: 22445348
references.citation: J Biol Chem. 1997 Apr 25;272(17):11313-20
references.pmid: 9111037
references.citation: Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2267-71
references.pmid: 1532254
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5
references.pmid: 19651612
references.citation: J Biol Chem. 2009 May 8;284(19):12845-52
references.pmid: 19282288
references.citation: Nat Cell Biol. 2009 May;11(5):510-20
references.pmid: 19404330
references.citation: J Neurosci. 2011 Feb 2;31(5):1644-51
references.pmid: 21289173
references.citation: Neuron. 2012 Mar 22;73(6):1204-15
references.pmid: 22445347
references.citation: PLoS One. 2012;7(2):e31302
references.pmid: 22312444
references.citation: Int J Alzheimers Dis. 2012;2012:172837
references.pmid: 22315694
references.citation: Nat Cell Biol. 2009 Jul;11(7):909-13
references.pmid: 19503072
references.citation: J Biol Chem. 2012 Dec 21;287(52):43223-33
references.pmid: 23129775
references.citation: Neuron. 2009 Apr 16;62(1):42-52
references.pmid: 19376066
references.citation: Nat Med. 2004 Mar;10(3):310-5
references.pmid: 14770178
references.citation: Nat Med. 2000 Dec;6(12):1380-7
references.pmid: 11100124
references.citation: J Neurosci. 2011 Sep 14;31(37):13110-7
references.pmid: 21917794
references.citation: Hum Mol Genet. 2006 Jul 1;15(13):2114-24
references.pmid: 16720620
references.citation: J Biol Chem. 2001 Feb 2;276(5):3254-61
references.pmid: 11024024
references.citation: Int J Biochem Cell Biol. 2008;40(9):1835-49
references.pmid: 18291704
references.citation: J Virol. 2004 May;78(10):4999-5006
references.pmid: 15113880
references.citation: J Mol Biol. 2007 May 11;368(4):982-97
references.pmid: 17382345
references.citation: J Control Release. 2005 Jan 20;102(1):247-53
references.pmid: 15653149
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3548-53
references.pmid: 21321227
references.citation: EMBO J. 1990 Dec;9(13):4225-30
references.pmid: 2124967
references.citation: Nat Cell Biol. 2009 Feb;11(2):219-25
references.pmid: 19151706
references.citation: AIDS. 1997 Oct;11(12):1421-31
references.pmid: 9342064
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20051-6
references.pmid: 19892735
references.citation: J Biol Chem. 2011 Apr 29;286(17):15317-31
references.pmid: 21372138
references.citation: Mol Ther. 2004 Dec;10(6):1011-22
references.pmid: 15564133
references.citation: J Biol Chem. 2005 Dec 9;280(49):40939-47
references.pmid: 16192266
references.citation: J Biol Chem. 2012 Aug 24;287(35):29722-8
references.pmid: 22753412
references.citation: Biochem Biophys Res Commun. 2007 Nov 9;363(1):95-100
references.pmid: 17826736
references.citation: FEBS Lett. 2008 May 28;582(12):1637-42
references.pmid: 18423405
references.citation: J Biol Chem. 2005 Apr 29;280(17):17062-7
references.pmid: 15668247
references.citation: J Neurosci. 2013 Jan 16;33(3):1024-37
references.pmid: 23325240
references.citation: Nature. 2003 Mar 6;422(6927):37-44
references.pmid: 12621426
references.citation: Biochemistry. 2002 Feb 5;41(5):1502-11
references.pmid: 11814343
references.citation: J Biol Chem. 2012 Jun 1;287(23):19440-51
references.pmid: 22461630
references.citation: Biochemistry. 2007 Jan 16;46(2):492-501
references.pmid: 17209559
references.citation: Neuron. 2012 Feb 23;73(4):685-97
references.pmid: 22365544
references.citation: Wound Repair Regen. 2008 Mar-Apr;16(2):294-9
references.pmid: 18318813
references.citation: Neuron. 2003 Nov 13;40(4):685-94
references.pmid: 14622574
references.citation: Nature. 1996 Oct 10;383(6600):550-3
references.pmid: 8849730