Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 08 2022
22 08 2022
Historique:
received:
01
03
2021
accepted:
10
08
2022
entrez:
22
8
2022
pubmed:
23
8
2022
medline:
25
8
2022
Statut:
epublish
Résumé
Considerable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson's disease, the molecular-cellular mechanism(s) remain unclear. To study this, we generated a new mouse model to specifically immunoisolate neuronal lysosomes, and established a long-term culture model where αSyn aggregates are produced within neurons without the addition of exogenous fibrils. We show that neuronally generated pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis. The released aggregates are non-membrane enveloped and seeding-competent. Additionally, we find that this release is dependent on neuronal activity and cytosolic Ca
Identifiants
pubmed: 35995799
doi: 10.1038/s41467-022-32625-1
pii: 10.1038/s41467-022-32625-1
pmc: PMC9395532
doi:
Substances chimiques
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4918Subventions
Organisme : NINDS NIH HHS
ID : RF1 NS126342
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102181
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS121077
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS113960
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG052505
Pays : United States
Organisme : NINDS NIH HHS
ID : F31 NS098623
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095988
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
J Cell Biol. 2000 Mar 20;148(6):1141-49
pubmed: 10725327
Science. 2017 Nov 10;358(6364):807-813
pubmed: 29074583
J Neurochem. 2006 Apr;97(1):265-79
pubmed: 16524375
Curr Protoc Cell Biol. 2001 May;Chapter 3:Unit 3.6
pubmed: 18228358
FASEB J. 2018 Feb;32(2):543-551
pubmed: 29101220
J Biol Chem. 2013 Jun 14;288(24):17313-35
pubmed: 23629650
Neuron. 2011 Oct 6;72(1):57-71
pubmed: 21982369
J Immunol Methods. 1989 Nov 30;124(2):205-10
pubmed: 2513357
Mol Neurodegener. 2012 Aug 24;7:42
pubmed: 22920859
J Neurol. 2002 Oct;249 Suppl 3:III/1-5
pubmed: 12528692
Cell. 2005 Nov 4;123(3):383-96
pubmed: 16269331
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5
pubmed: 19651612
Autophagy. 2018;14(1):98-119
pubmed: 29198173
Science. 2012 Nov 16;338(6109):949-53
pubmed: 23161999
Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9564-8
pubmed: 7937806
Mol Neurodegener. 2018 Feb 22;13(1):9
pubmed: 29467003
PLoS One. 2012;7(1):e29729
pubmed: 22235333
Neuroscience. 2003;118(4):985-1002
pubmed: 12732244
N Engl J Med. 2009 Oct 22;361(17):1651-61
pubmed: 19846850
Nat Rev Neurol. 2020 Apr;16(4):199-212
pubmed: 32203399
J Virol. 1998 Nov;72(11):8463-71
pubmed: 9765382
Clin Genet. 2013 Jun;83(6):571-5
pubmed: 22978711
Mol Neurobiol. 2022 Jan;59(1):405-419
pubmed: 34705229
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6469-73
pubmed: 9600990
J Biol Chem. 2004 May 7;279(19):20471-9
pubmed: 14993220
Glia. 2014 Mar;62(3):387-98
pubmed: 24382629
Nature. 1997 Aug 28;388(6645):839-40
pubmed: 9278044
Science. 2002 Feb 1;295(5556):868-72
pubmed: 11786607
PLoS One. 2011;6(11):e26741
pubmed: 22073189
J Biol Chem. 2005 Jul 1;280(26):25216-24
pubmed: 15863497
Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
pubmed: 12498954
Neurobiol Dis. 2015 Oct;82:185-199
pubmed: 26093169
Am J Hum Genet. 2011 Aug 12;89(2):241-52
pubmed: 21820099
EMBO J. 2016 Oct 4;35(19):2120-2138
pubmed: 27550960
Mol Endocrinol. 1998 Jul;12(7):1060-70
pubmed: 9658409
J Med Genet. 2004 Dec;41(12):937-40
pubmed: 15591280
Brain. 2018 Aug 1;141(8):2255-2262
pubmed: 29860491
Acta Neuropathol. 2018 Jan;135(1):65-83
pubmed: 29209768
Neurosci Lett. 2000 Jun 16;287(1):65-7
pubmed: 10841992
Lancet Neurol. 2018 Nov;17(11):1016-1024
pubmed: 30353860
Acta Neuropathol. 2017 Nov;134(5):789-808
pubmed: 28725967
Res Commun Chem Pathol Pharmacol. 1985 Dec;50(3):435-41
pubmed: 3878557
Nat Med. 2008 May;14(5):501-3
pubmed: 18391963
Science. 2010 Sep 24;329(5999):1663-7
pubmed: 20798282
Mov Disord. 2011 Aug 1;26(9):1593-604
pubmed: 21618611
Mol Brain. 2019 Nov 29;12(1):100
pubmed: 31783880
J Neurosci. 2015 Apr 1;35(13):5221-32
pubmed: 25834048
PLoS Biol. 2021 Jul 20;19(7):e3001287
pubmed: 34283825
J Neurosci. 2005 Jun 22;25(25):6016-24
pubmed: 15976091
FASEB J. 2003 Oct;17(13):1945-7
pubmed: 14519670
Science. 2018 May 18;360(6390):751-758
pubmed: 29700228
J Neurochem. 2010 Jun;113(5):1263-74
pubmed: 20345754
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20051-6
pubmed: 19892735
Neuron. 2004 Apr 22;42(2):237-51
pubmed: 15091340
J Neurosci. 2010 May 19;30(20):6838-51
pubmed: 20484626
Biochem Biophys Res Commun. 2008 Aug 1;372(3):423-8
pubmed: 18492487
Acta Neuropathol. 2013 Oct;126(4):555-73
pubmed: 23925565
J Vis Exp. 2018 Mar 19;(133):
pubmed: 29608146
Proc Natl Acad Sci U S A. 2014 May 27;111(21):7671-6
pubmed: 24817693
J Neurobiol. 2002 Apr;51(1):9-23
pubmed: 11920724
Nat Med. 2008 May;14(5):504-6
pubmed: 18391962
Nat Struct Mol Biol. 2020 Feb;27(2):192-201
pubmed: 32042150
Elife. 2019 Oct 30;8:
pubmed: 31663851
Am J Pathol. 1998 Apr;152(4):879-84
pubmed: 9546347
Neurobiol Dis. 2019 Dec;132:104587
pubmed: 31454546
Acta Neuropathol Commun. 2017 Jun 9;5(1):46
pubmed: 28599681
Neurobiol Dis. 2011 Jul;43(1):17-28
pubmed: 20732422
J Cell Biol. 2000 May 15;149(4):889-900
pubmed: 10811829
Sci Rep. 2013;3:2540
pubmed: 23985836
J Biochem. 1991 Oct;110(4):541-7
pubmed: 1663946