A cullin-RING ubiquitin ligase targets exogenous α-synuclein and inhibits Lewy body-like pathology.
Animals
Benzothiazoles
/ metabolism
COS Cells
Cell Line, Tumor
Chlorocebus aethiops
Humans
Lewy Bodies
/ metabolism
Mice
Neuroblastoma
/ metabolism
Neurons
/ metabolism
Parkinson Disease
/ metabolism
Proteome
/ metabolism
S-Phase Kinase-Associated Proteins
/ metabolism
Ubiquitin
/ metabolism
Ubiquitin-Protein Ligases
/ metabolism
alpha-Synuclein
/ metabolism
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
05 06 2019
05 06 2019
Historique:
received:
04
07
2018
revised:
16
11
2018
accepted:
08
05
2019
entrez:
7
6
2019
pubmed:
7
6
2019
medline:
1
7
2020
Statut:
ppublish
Résumé
Parkinson's disease (PD) is a neurological disorder characterized by the progressive accumulation of neuronal α-synuclein (αSyn) inclusions called Lewy bodies. It is believed that Lewy bodies spread throughout the nervous system due to the cell-to-cell propagation of αSyn via cycles of secretion and uptake. Here, we investigated the internalization and intracellular accumulation of exogenous αSyn, two key steps of Lewy body pathogenesis, amplification and spreading. We found that stable αSyn fibrils substantially accumulate in different cell lines upon internalization, whereas αSyn monomers, oligomers, and dissociable fibrils do not. Our data indicate that the uptake-mediated accumulation of αSyn in a human-derived neuroblastoma cell line triggered an adaptive response that involved proteins linked to ubiquitin ligases of the S-phase kinase-associated protein 1 (SKP1), cullin-1 (Cul1), and F-box domain-containing protein (SCF) family. We found that SKP1, Cul1, and the F-box/LRR repeat protein 5 (FBXL5) colocalized and physically interacted with internalized αSyn in cultured cells. Moreover, the SCF containing the F-box protein FBXL5 (SCF
Identifiants
pubmed: 31167929
pii: 11/495/eaau6722
doi: 10.1126/scitranslmed.aau6722
pmc: PMC10697662
mid: NIHMS1938885
pii:
doi:
Substances chimiques
Benzothiazoles
0
Proteome
0
S-Phase Kinase-Associated Proteins
0
Ubiquitin
0
alpha-Synuclein
0
thioflavin T
2390-54-7
CULL-RING ligase, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Intramural NIH HHS
ID : Z99 AG999999
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AG000936
Pays : United States
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Références
J Biol Chem. 2013 Mar 1;288(9):6371-85
pubmed: 23319586
Nature. 2009 Apr 9;458(7239):732-6
pubmed: 19360080
Nat Med. 2008 May;14(5):504-6
pubmed: 18391962
Nature. 2011 Aug 14;477(7362):107-10
pubmed: 21841800
J Neural Transm (Vienna). 2004 Dec;111(12):1543-73
pubmed: 15455214
Hum Mol Genet. 2016 Mar 15;25(6):1100-15
pubmed: 26740557
Science. 2004 Aug 27;305(5688):1292-5
pubmed: 15333840
Nat Cell Biol. 2002 Feb;4(2):160-4
pubmed: 11813001
Biochemistry. 2000 Mar 14;39(10):2552-63
pubmed: 10704204
Exp Neurol. 2006 Apr;198(2):382-90
pubmed: 16455076
Cell Rep. 2016 Oct 18;17(4):931-940
pubmed: 27760323
Science. 1997 Jun 27;276(5321):2045-7
pubmed: 9197268
Nat Methods. 2007 Mar;4(3):207-14
pubmed: 17327847
J Neurosci. 2011 Oct 12;31(41):14508-20
pubmed: 21994367
J Biol Chem. 2014 Jun 27;289(26):18137-51
pubmed: 24831002
Expert Opin Ther Targets. 2012 Apr;16(4):421-32
pubmed: 22480256
J Neurosci. 2009 Feb 4;29(5):1480-5
pubmed: 19193894
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5500-5
pubmed: 15064394
Mol Ther. 2010 Aug;18(8):1450-7
pubmed: 20551914
Science. 2003 Oct 31;302(5646):841
pubmed: 14593171
J Neurosci. 2012 Sep 26;32(39):13454-69
pubmed: 23015436
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5
pubmed: 19651612
J Neurochem. 2017 Feb;140(4):662-678
pubmed: 27424880
Science. 2012 Nov 16;338(6109):949-53
pubmed: 23161999
Front Neurosci. 2016 Jan 29;10:12
pubmed: 26858591
Cell Metab. 2011 Sep 7;14(3):339-51
pubmed: 21907140
J Biol Chem. 1999 Nov 26;274(48):33855-8
pubmed: 10567343
J Am Chem Soc. 2012 Mar 28;134(12):5468-71
pubmed: 22404520
J Biol Chem. 2010 Mar 19;285(12):9262-72
pubmed: 20071342
PLoS One. 2013 Apr 25;8(4):e62143
pubmed: 23634225
Biochim Biophys Acta. 2014 Jan;1843(1):47-60
pubmed: 23747565
Neurotox Res. 2018 Apr;33(3):560-568
pubmed: 29218503
PLoS One. 2011 Feb 16;6(2):e14695
pubmed: 21358815
J Clin Invest. 2015 Jul 1;125(7):2721-35
pubmed: 26075822
Am J Pathol. 2001 Dec;159(6):2215-25
pubmed: 11733371
Neuron. 2005 Jun 16;46(6):857-68
pubmed: 15953415
Nat Genet. 1998 Feb;18(2):106-8
pubmed: 9462735
Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9
pubmed: 15451224
J Exp Med. 2012 May 7;209(5):975-86
pubmed: 22508839
FEBS Lett. 2001 Nov 30;509(1):22-6
pubmed: 11734199
Mol Neurodegener. 2015 Oct 31;10:57
pubmed: 26520394
J Biol Chem. 2013 May 24;288(21):15194-210
pubmed: 23532841
Science. 2017 Sep 1;357(6354):891-898
pubmed: 28860381
Glia. 2014 Mar;62(3):387-98
pubmed: 24382629
Nature. 1997 Aug 28;388(6645):839-40
pubmed: 9278044
Nat Genet. 2009 Dec;41(12):1308-12
pubmed: 19915575
Chem Biol. 2013 Oct 24;20(10):1207-13
pubmed: 24210006
Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17726-31
pubmed: 24043770
Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
pubmed: 12498954
Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18666-71
pubmed: 22065755
Acta Neuropathol Commun. 2013 Jul 17;1:38
pubmed: 24252149
Mol Neurodegener. 2007 Sep 26;2:18
pubmed: 17897471
Science. 2001 Jul 13;293(5528):263-9
pubmed: 11431533
Ann Neurol. 1998 Sep;44(3):415-22
pubmed: 9749615
Int J Biochem Cell Biol. 2008;40(9):1835-49
pubmed: 18291704
Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17004-9
pubmed: 21953697
PLoS One. 2010 Aug 11;5(8):e12122
pubmed: 20711464
Nat Genet. 2009 Dec;41(12):1303-7
pubmed: 19915576
Parkinsonism Relat Disord. 2014 Jan;20 Suppl 1:S85-7
pubmed: 24262196
Nat Protoc. 2014 Sep;9(9):2135-46
pubmed: 25122523
Mol Ther. 2014 Oct;22(10):1753-67
pubmed: 25008355
J Mol Biol. 2009 Nov 20;394(1):94-107
pubmed: 19747490
Exp Neurol. 2008 Jan;209(1):22-7
pubmed: 17949715
Neuron. 2010 Jan 14;65(1):66-79
pubmed: 20152114
Science. 2009 Oct 30;326(5953):722-6
pubmed: 19762597
Nat Med. 2008 May;14(5):501-3
pubmed: 18391963
Science. 2010 Sep 24;329(5999):1663-7
pubmed: 20798282
J Neurosci Res. 2002 Jun 1;68(5):568-78
pubmed: 12111846
Nat Cell Biol. 1999 Aug;1(4):193-9
pubmed: 10559916
Nature. 2013 Jun 13;498(7453):E4-6; discussion E6-7
pubmed: 23765500
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20051-6
pubmed: 19892735
Biomed Res Int. 2014;2014:581256
pubmed: 24527451
Mol Cell. 2008 Oct 10;32(1):21-31
pubmed: 18851830
Mov Disord. 2013 Jan;28(1):61-70
pubmed: 22753348
Biochem Biophys Res Commun. 2008 Aug 1;372(3):423-8
pubmed: 18492487
Acta Neuropathol. 2013 Oct;126(4):555-73
pubmed: 23925565
J Mol Biol. 2008 Feb 1;375(5):1394-404
pubmed: 18082181
Nature. 2015 Sep 24;525(7570):486-90
pubmed: 26352473
J Biol Chem. 2007 Feb 23;282(8):5641-52
pubmed: 17182613
J Parkinsons Dis. 2012;2(4):249-67
pubmed: 23938255
Am J Pathol. 1998 Apr;152(4):879-84
pubmed: 9546347
Nat Med. 1998 Nov;4(11):1318-20
pubmed: 9809558
Nat Rev Mol Cell Biol. 2013 Jun;14(6):369-81
pubmed: 23657496
Science. 2009 Oct 30;326(5953):718-21
pubmed: 19762596
J Biol Chem. 2008 Jun 27;283(26):17962-8
pubmed: 18436529
Mol Neurodegener. 2008 Nov 01;3:19
pubmed: 18976489
J Biol Chem. 2003 Jul 4;278(27):25009-13
pubmed: 12719433
Cell Death Differ. 2011 Sep;18(9):1425-33
pubmed: 21566660
FASEB J. 2005 Apr;19(6):533-42
pubmed: 15791003
Nat Rev Drug Discov. 2014 Dec;13(12):889-903
pubmed: 25394868
Cell. 2008 Sep 19;134(6):995-1006
pubmed: 18805092
J Biol Chem. 2002 Dec 13;277(50):49071-6
pubmed: 12377775
Acta Neuropathol. 2014 May;127(5):645-65
pubmed: 24659240
Neuron. 2011 Oct 6;72(1):57-71
pubmed: 21982369
J Biol Chem. 2001 Jul 20;276(29):27441-8
pubmed: 11316809
Cell Rep. 2014 Jun 26;7(6):2054-65
pubmed: 24931606
Mol Neurodegener. 2012 May 31;7:26
pubmed: 22651796
Mov Disord. 2012 Jun;27(7):831-42
pubmed: 22451330
Acta Neuropathol. 2017 Oct;134(4):629-653
pubmed: 28527044
Front Hum Neurosci. 2016 Dec 02;10:608
pubmed: 27994545
Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S148-51
pubmed: 20082978
Cell Death Dis. 2012 Nov 22;3:e428
pubmed: 23171848
J Biol Chem. 2006 Oct 6;281(40):29739-52
pubmed: 16847063