title: Axonal transport and secretion of fibrillar forms of α-synuclein, Aβ42 peptide and HTTExon 1.
abstract: Accruing evidence suggests that prion-like behavior of fibrillar forms of α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread of the lesions that characterize Parkinson disease, Alzheimer disease and Huntington disease, respectively. It is unknown whether these distinct protein assemblies are transported within and between neurons by similar or distinct mechanisms. It is also unclear if neuronal death or injury is required for neuron-to-neuron transfer. To address these questions, we used mouse primary cortical neurons grown in microfluidic devices to measure the amounts of α-synuclein, Aβ42 and HTTExon1 fibrils transported by axons in both directions (anterograde and retrograde), as well as to examine the mechanism of their release from axons after anterograde transport. We observed that the three fibrils were transported in both anterograde and retrograde directions but with strikingly different efficiencies. The amount of Aβ42 fibrils transported was ten times higher than that of the other two fibrils. HTTExon1 was efficiently transported in the retrograde direction but only marginally in the anterograde direction. Finally, using neurons from two distinct mutant mouse strains whose axons are highly resistant to neurodegeneration (Wld(S) and Sarm1(-/-)), we found that the three different fibrils were secreted by axons after anterograde transport, in the absence of axonal lysis, indicating that trans-neuronal spread can occur in intact healthy neurons. In summary, fibrils of α-synuclein, Aβ42 and HTTExon1 are all transported in axons but in directions and amounts that are specific of each fibril. After anterograde transport, the three fibrils were secreted in the medium in the absence of axon lysis. Continuous secretion could play an important role in the spread of pathology between neurons but may be amenable to pharmacological intervention.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305-5120, USA. mbrahic@stanford.edu.
authors.forename: Michel
authors.initials: M
authors.lastname: Brahic
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Gif-sur-Yvette, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Bousset
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305-5120, USA.|Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bieri
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Gif-sur-Yvette, France.
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305-5120, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism; D001370:Axonal Transport / Q000502:physiology*; D001921:Brain / Q000473:pathology; D002772:Cholera Toxin / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism*; D056656:Lab-On-A-Chip Devices; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D010454:Peptide Termination Factors / Q000378:metabolism; D011099:Polyglutamic Acid / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D046912:Multiprotein Complexes; D010446:Peptide Fragments; D010454:Peptide Termination Factors; D011328:Prions; C543961:SARM1 protein, mouse; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D011099:Polyglutamic Acid; D002772:Cholera Toxin; D005979:Glutathione Peroxidase; C067020:URE2 protein, S cerevisiae
keywords: Axonal transport; Aβ42; HTTExon1; Secretion; α-Synuclein
references.citation: Nature. 2015 Jun 18;522(7556):340-4
references.pmid: 26061766
references.citation: Neuron. 2012 Feb 23;73(4):685-97
references.pmid: 22365544
references.citation: Neurology. 2002 Jun 25;58(12):1791-800
references.pmid: 12084879
references.citation: Am J Pathol. 2002 Nov;161(5):1869-79
references.pmid: 12414533
references.citation: J Neurol. 2002 Oct;249 Suppl 3:III/1-5
references.pmid: 12528692
references.citation: J Neural Transm (Vienna). 2003 May;110(5):517-36
references.pmid: 12721813
references.citation: J Neurosci. 2003 Oct 1;23(26):8967-77
references.pmid: 14523099
references.citation: N Engl J Med. 1984 Mar 8;310(10):661-3
references.pmid: 6363926
references.citation: J Neurosci Methods. 1988 Jul;24(3):225-35
references.pmid: 2458510
references.citation: Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9717-20
references.pmid: 8415768
references.citation: J Neurosci Methods. 1996 Mar;65(1):101-12
references.pmid: 8815303
references.citation: J Biol Chem. 1999 May 7;274(19):13666-74
references.pmid: 10224139
references.citation: Nat Methods. 2005 Aug;2(8):599-605
references.pmid: 16094385
references.citation: FEBS J. 2005 Aug;272(16):4023-33
references.pmid: 16098186
references.citation: Neurobiol Aging. 2005 Oct;26(9):1235-44
references.pmid: 16023263
references.citation: EMBO J. 2006 Feb 22;25(4):822-33
references.pmid: 16467849
references.citation: J Neurosci. 2007 Mar 21;27(12):3131-8
references.pmid: 17376974
references.citation: Sci STKE. 2007 Dec 18;2007(417):pe73
references.pmid: 18089857
references.citation: Nat Med. 2008 May;14(5):501-3
references.pmid: 18391963
references.citation: Nat Cell Biol. 2009 Feb;11(2):219-25
references.pmid: 19151706
references.citation: FEBS J. 2009 Mar;276(5):1266-81
references.pmid: 19175671
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5907-12
references.pmid: 19321417
references.citation: Nat Cell Biol. 2009 Jul;11(7):909-13
references.pmid: 19503072
references.citation: J Neurochem. 2009 Oct;111(1):192-203
references.pmid: 19686384
references.citation: Exp Neurol. 2009 Dec;220(2):224-5
references.pmid: 19786018
references.citation: Nat Commun. 2013;4:2575
references.pmid: 24108358
references.citation: Neuroscientist. 2014 Feb;20(1):71-81
references.pmid: 23912032
references.citation: Ann Neurol. 2014 Jul;76(1):31-42
references.pmid: 24798518
references.citation: Nat Neurosci. 2014 Aug;17(8):1064-72
references.pmid: 25017010
references.citation: J Neurosci. 2014 Nov 12;34(46):15281-7
references.pmid: 25392495
references.citation: Hum Mol Genet. 2014 Dec 20;23(25):6732-45
references.pmid: 25092884
references.citation: J Biol Chem. 2015 Jan 30;290(5):2560-76
references.pmid: 25505179
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20051-6
references.pmid: 19892735
references.citation: J Cell Sci. 2010 Apr 15;123(Pt 8):1191-201
references.pmid: 20356930
references.citation: J Neurosci. 2010 May 19;30(20):6838-51
references.pmid: 20484626
references.citation: J Neurosci. 2010 Jul 7;30(27):9166-71
references.pmid: 20610750
references.citation: J Biol Chem. 2010 Nov 5;285(45):34885-98
references.pmid: 20805224
references.citation: Science. 2010 Nov 12;330(6006):980-2
references.pmid: 20966215
references.citation: J Clin Invest. 2011 Feb;121(2):715-25
references.pmid: 21245577
references.citation: Traffic. 2012 May;13(5):681-93
references.pmid: 22309053
references.citation: J Exp Med. 2012 May 7;209(5):975-86
references.pmid: 22508839
references.citation: J Biol Chem. 2012 Jun 1;287(23):19440-51
references.pmid: 22461630
references.citation: Biophys J. 2012 Jun 20;102(12):2894-905
references.pmid: 22735540
references.citation: Science. 2012 Jul 27;337(6093):481-4
references.pmid: 22678360
references.citation: Ann Neurol. 2012 Oct;72(4):517-24
references.pmid: 23109146
references.citation: Science. 2012 Nov 16;338(6109):949-53
references.pmid: 23161999
references.citation: J Biol Chem. 2013 Jan 18;288(3):1856-70
references.pmid: 23188818
references.citation: Cell. 2013 Sep 12;154(6):1182-4
references.pmid: 24034239
references.citation: Cell. 2013 Sep 12;154(6):1257-68
references.pmid: 24034249
references.citation: Acta Neuropathol Commun. 2015;3:13
references.pmid: 25853980
references.citation: Neurobiol Dis. 2011 Jun;42(3):360-7
references.pmid: 21303699
references.citation: Neuron. 2011 May 12;70(3):441-54
references.pmid: 21555071
references.citation: Neuron. 2011 Oct 6;72(1):57-71
references.pmid: 21982369
references.citation: J Cell Biol. 2012 Jan 9;196(1):7-18
references.pmid: 22232700
references.citation: Neuropathol Appl Neurobiol. 2016 Feb;42(2):137-52
references.pmid: 26111612