A light-inducible protein clustering system for in vivo analysis of α-synuclein aggregation in Parkinson disease.
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
22
09
2021
accepted:
18
02
2022
revised:
21
03
2022
pubmed:
10
3
2022
medline:
21
4
2022
entrez:
9
3
2022
Statut:
epublish
Résumé
Neurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of α-synuclein (α-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of α-syn aggregation in PD.
Identifiants
pubmed: 35263320
doi: 10.1371/journal.pbio.3001578
pii: PBIOLOGY-D-21-02530
pmc: PMC8936469
doi:
Substances chimiques
Protein Aggregates
0
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3001578Subventions
Organisme : CIHR
Pays : Canada
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Exp Brain Res. 1999 Apr;125(4):397-409
pubmed: 10323285
Neuron. 2019 Apr 17;102(2):321-338.e8
pubmed: 30826182
Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):E912-21
pubmed: 26839406
Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):E3945-54
pubmed: 23983262
J Neurochem. 2021 May;157(4):891-898
pubmed: 33336386
J Biol Chem. 2001 Jan 26;276(4):2380-6
pubmed: 11060312
Prog Brain Res. 2010;183:115-45
pubmed: 20696318
J Biol Chem. 2006 Oct 6;281(40):29739-52
pubmed: 16847063
Nat Rev Neurosci. 2013 Jan;14(1):38-48
pubmed: 23254192
Nat Rev Neurosci. 2021 Feb;22(2):111-131
pubmed: 33432241
Trends Neurosci. 1989 Oct;12(10):366-75
pubmed: 2479133
Nat Cell Biol. 2002 Feb;4(2):160-4
pubmed: 11813001
Exp Neurobiol. 2014 Dec;23(4):324-36
pubmed: 25548532
CNS Neurol Disord Drug Targets. 2015;14(7):947-55
pubmed: 25801839
J Parkinsons Dis. 2011;1(3):277-86
pubmed: 23939308
Anat Rec. 1991 Dec;231(4):482-97
pubmed: 1793176
Clin Neurophysiol. 2008 Jul;119(7):1459-74
pubmed: 18467168
Exp Mol Med. 2017 Apr 7;49(4):e314
pubmed: 28386127
Nat Commun. 2017 Jun 23;8(1):30
pubmed: 28646204
J Neurosci Methods. 2002 Jan 30;113(2):123-30
pubmed: 11772434
Neuropharmacology. 2000 Mar 3;39(5):777-87
pubmed: 10699444
Nat Rev Neurosci. 2009 Jul;10(7):519-29
pubmed: 19513088
J Neurol Neurosurg Psychiatry. 1988 Jun;51(6):745-52
pubmed: 2841426
Brain Res. 2008 Jan 23;1190:78-85
pubmed: 18073128
Trends Neurosci. 1990 Jul;13(7):281-5
pubmed: 1695404
Nat Rev Neurosci. 2013 Sep;14(9):626-36
pubmed: 23900411
Neuroscience. 2011 Dec 15;198:232-44
pubmed: 21723919
Brain. 2014 May;137(Pt 5):1496-513
pubmed: 24662516
Neuron. 2013 Jun 5;78(5):785-98
pubmed: 23764284
Acta Neuropathol Commun. 2019 Mar 14;7(1):41
pubmed: 30871620
Nature. 1997 Aug 28;388(6645):839-40
pubmed: 9278044
Nat Commun. 2020 Feb 21;11(1):1004
pubmed: 32081878
Mol Neurobiol. 2013 Apr;47(2):495-508
pubmed: 22622968
Neuron. 2001 Oct 25;32(2):213-23
pubmed: 11683992
PLoS One. 2013 Oct 11;8(10):e77235
pubmed: 24146972
Eur J Neurosci. 2002 Dec;16(11):2136-48
pubmed: 12473081
Trends Neurosci. 2003 Apr;26(4):215-21
pubmed: 12689773
Elife. 2019 Mar 06;8:
pubmed: 30839276
Biochem Soc Trans. 2013 Oct;41(5):1183-8
pubmed: 24059506
Prog Neurobiol. 1998 Jun;55(2):93-116
pubmed: 9618745
PLoS One. 2015 Oct 20;10(10):e0140880
pubmed: 26484876
Lancet Neurol. 2004 Aug;3(8):496-503
pubmed: 15261611
EMBO J. 2012 Feb 1;31(3):640-53
pubmed: 22068054
Cell. 2017 Jan 12;168(1-2):159-171.e14
pubmed: 28041848
Nat Commun. 2014 Sep 18;5:4925
pubmed: 25233328
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1661-8
pubmed: 16449387
J Biol Chem. 2004 Jun 25;279(26):26846-57
pubmed: 15096521
Eur J Neurosci. 2007 Sep;26(6):1701-13
pubmed: 17880401
J Neurosci Res. 2002 Jun 1;68(5):568-78
pubmed: 12111846
Nat Med. 2014 Feb;20(2):130-8
pubmed: 24504409
Neurology. 2019 Feb 12;92(7):329-337
pubmed: 30745444
Nat Neurosci. 2019 Jul;22(7):1099-1109
pubmed: 31235907
Clin Chem Lab Med. 2001 Nov;39(11):1065-75
pubmed: 11831622
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20051-6
pubmed: 19892735
Brain Res Brain Res Protoc. 1997 Dec 1;2(1):75-84
pubmed: 9438075
Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):E1009-E1017
pubmed: 28096355
Nat Rev Neurol. 2013 Jan;9(1):13-24
pubmed: 23183883
Cell Rep. 2019 Jul 2;28(1):65-77.e6
pubmed: 31269451
Neurobiol Dis. 2015 Sep;81:76-92
pubmed: 25497688
Biomolecules. 2019 Feb 12;9(2):
pubmed: 30759894
Elife. 2020 Mar 31;9:
pubmed: 32228858
Nature. 2020 Feb;578(7794):273-277
pubmed: 32025029
Sci Adv. 2021 May 14;7(20):
pubmed: 33990334
Brain Res. 1997 Nov 14;775(1-2):24-9
pubmed: 9439824
J Biol Chem. 2002 Dec 13;277(50):49071-6
pubmed: 12377775
Sci Rep. 2016 Nov 03;6:36010
pubmed: 27808107
Prion. 2020 Dec;14(1):88-94
pubmed: 32041499
Biochemistry. 2006 May 16;45(19):6085-94
pubmed: 16681381