title: Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson's disease.
abstract: Lewy bodies (LBs) are intraneuronal inclusions consisting primarily of fibrillized human α-synuclein (hα-Syn) protein, which represent the major pathological hallmark of Parkinson's disease (PD). Although doubling hα-Syn expression provokes LB pathology in humans, hα-Syn overexpression does not trigger the formation of fibrillar LB-like inclusions in mice. We hypothesized that interactions between exogenous hα-Syn and endogenous mouse synuclein homologs could be attenuating hα-Syn fibrillization in mice, and therefore, we systematically assessed hα-Syn aggregation propensity in neurons derived from α-Syn-KO, β-Syn-KO, γ-Syn-KO, and triple-KO mice lacking expression of all three synuclein homologs. Herein, we show that hα-Syn forms hyperphosphorylated (at S129) and ubiquitin-positive LB-like inclusions in primary neurons of α-Syn-KO, β-Syn-KO, and triple-KO mice, as well as in transgenic α-Syn-KO mouse brains in vivo. Importantly, correlative light and electron microscopy, immunogold labeling, and thioflavin-S binding established their fibrillar ultrastructure, and fluorescence recovery after photobleaching/photoconversion experiments showed that these inclusions grow in size and incorporate soluble proteins. We further investigated whether the presence of homologous α-Syn species would interfere with the seeding and spreading of α-Syn pathology. Our results are in line with increasing evidence demonstrating that the spreading of α-Syn pathology is most prominent when the injected preformed fibrils and host-expressed α-Syn monomers are from the same species. These findings provide insights that will help advance the development of neuronal and in vivo models for understanding mechanisms underlying hα-Syn intraneuronal fibrillization and its contribution to PD pathogenesis, and for screening pharmacologic and genetic modulators of α-Syn fibrillization in neurons.
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland;
authors.forename: Mohamed-Bilal
authors.initials: MB
authors.lastname: Fares
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland;
authors.forename: Bohumil
authors.initials: B
authors.lastname: Maco
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland;
authors.forename: Abid
authors.initials: A
authors.lastname: Oueslati
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093;
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, CF10 3AX, United Kingdom;
authors.forename: Natalia
authors.initials: N
authors.lastname: Ninkina
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, CF10 3AX, United Kingdom;
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Buchman
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093;
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland; Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, 5825, Qatar hilal.lashuel@epfl.ch.
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein
keywords: Parkinson’s disease; aggregation; alpha-synuclein
references.citation: Nat Rev Neurosci. 2013 Jan;14(1):38-48
references.pmid: 23254192
references.citation: Science. 2001 Sep 28;293(5539):2459-62
references.pmid: 11577236
references.citation: Mol Neurodegener. 2009 Feb 04;4:9
references.pmid: 19193223
references.citation: Biophys Chem. 2010 Aug;150(1-3):73-9
references.pmid: 20153100
references.citation: Nature. 2015 Jun 18;522(7556):340-4
references.pmid: 26061766
references.citation: J Neurosci. 2006 Apr 12;26(15):3942-50
references.pmid: 16611810
references.citation: Neurobiol Dis. 2006 Mar;21(3):541-8
references.pmid: 16298531
references.citation: Neuron. 2000 Jan;25(1):239-52
references.pmid: 10707987
references.citation: Neuron. 2010 Jun 10;66(5):646-61
references.pmid: 20547124
references.citation: J Biol Chem. 2002 Feb 15;277(7):5411-7
references.pmid: 11724769
references.citation: Acta Neuropathol Commun. 2014;2:88
references.pmid: 25095794
references.citation: J Biol Chem. 2002 Dec 13;277(50):49071-6
references.pmid: 12377775
references.citation: Neuroscience. 2002;113(2):463-78
references.pmid: 12127102
references.citation: J Neurosci. 2011 May 18;31(20):7264-74
references.pmid: 21593311
references.citation: Nat Methods. 2009 Feb;6(2):131-3
references.pmid: 19169260
references.citation: Brain Res. 1994 Jan 21;634(2):339-44
references.pmid: 8131084
references.citation: Nat Genet. 1999 May;22(1):110-4
references.pmid: 10319874
references.citation: J Biol Chem. 2012 Aug 17;287(34):28243-62
references.pmid: 22718772
references.citation: J Neurochem. 2008 Jul;106(2):529-40
references.pmid: 18410502
references.citation: Neuron. 2001 Oct 25;32(2):213-23
references.pmid: 11683992
references.citation: Neurobiol Dis. 2015 Oct;82:185-99
references.pmid: 26093169
references.citation: Science. 2000 Feb 18;287(5456):1265-9
references.pmid: 10678833
references.citation: J Biol Chem. 2004 Feb 6;279(6):4625-31
references.pmid: 14627698
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14966-71
references.pmid: 15465911
references.citation: Neuroscience. 2001;104(3):901-12
references.pmid: 11440819
references.citation: Hum Mol Genet. 2014 Sep 1;23(17):4491-509
references.pmid: 24728187
references.citation: PLoS One. 2011;6(8):e23338
references.pmid: 21858077
references.citation: Biochemistry. 2000 Sep 5;39(35):10619-26
references.pmid: 10978144
references.citation: Acta Neuropathol Commun. 2013;1:38
references.pmid: 24252149
references.citation: Biochemistry. 1999 Nov 23;38(47):15514-21
references.pmid: 10569934
references.citation: J Neurochem. 2004 Jun;89(5):1126-36
references.pmid: 15147505
references.citation: PLoS Genet. 2014 May;10(5):e1004302
references.pmid: 24810576
references.citation: J Mol Biol. 2010 Sep 3;401(5):776-91
references.pmid: 20603133
references.citation: J Neurosci. 2012 Feb 1;32(5):1536-44
references.pmid: 22302797
references.citation: J Biol Chem. 2002 Apr 5;277(14):11970-8
references.pmid: 11812782
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6469-73
references.pmid: 9600990
references.citation: Biochemistry. 2010 Feb 9;49(5):872-81
references.pmid: 20028124
references.citation: J Neurosci. 2010 Mar 3;30(9):3184-98
references.pmid: 20203178
references.citation: J Neurosci. 2014 Sep 10;34(37):12368-78
references.pmid: 25209277
references.citation: Nat Rev Neurosci. 2013 Sep;14(9):626-36
references.pmid: 23900411
references.citation: J Exp Med. 2012 May 7;209(5):975-86
references.pmid: 22508839
references.citation: Am J Pathol. 2002 Nov;161(5):1935-48
references.pmid: 12414539
references.citation: Nature. 1997 Aug 28;388(6645):839-40
references.pmid: 9278044
references.citation: J Neurosci. 2001 Oct 15;21(20):8053-61
references.pmid: 11588178
references.citation: Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10732-7
references.pmid: 25002524
references.citation: Nature. 2000 Mar 23;404(6776):394-8
references.pmid: 10746727
references.citation: BMC Neurosci. 2001;2:11
references.pmid: 11591219
references.citation: Nat Cell Biol. 2002 Feb;4(2):160-4
references.pmid: 11813001
references.citation: Hum Mol Genet. 2000 Nov 1;9(18):2683-9
references.pmid: 11063727
references.citation: J Neurosci. 1998 Nov 15;18(22):9335-41
references.pmid: 9801372
references.citation: Science. 2012 Nov 16;338(6109):949-53
references.pmid: 23161999
references.citation: Acta Neuropathol Commun. 2014;2:29
references.pmid: 24624994
references.citation: Prog Brain Res. 2010;183:115-45
references.pmid: 20696318
references.citation: Neurobiol Aging. 2005 Jan;26(1):25-35
references.pmid: 15585343
references.citation: Hum Mol Genet. 2006 Oct 15;15(20):3002-11
references.pmid: 16959793
references.citation: Biochemistry. 2003 Apr 8;42(13):3696-700
references.pmid: 12667059
references.citation: FEBS Lett. 2001 Nov 30;509(1):22-6
references.pmid: 11734199
references.citation: Neuron. 2011 Oct 6;72(1):57-71
references.pmid: 21982369
references.citation: Science. 1995 May 26;268(5214):1142-3
references.pmid: 7539154
references.citation: Neuron. 2002 Dec 19;36(6):1007-19
references.pmid: 12495618
references.citation: J Biol Chem. 2010 May 14;285(20):14941-54
references.pmid: 20150427
references.citation: J Neuropathol Exp Neurol. 2008 Nov;67(11):1084-96
references.pmid: 18957893
references.citation: J Biol Chem. 2014 Aug 8;289(32):21856-76
references.pmid: 24936070