Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans.
Alpha-synuclein
Animal model
Artificial intelligence
Drug discovery
Machine learning
Natural language processing
Neurodegeneration
Oligomers
Parkinson’s disease
Journal
Molecular neurodegeneration
ISSN: 1750-1326
Titre abrégé: Mol Neurodegener
Pays: England
ID NLM: 101266600
Informations de publication
Date de publication:
12 11 2021
12 11 2021
Historique:
received:
04
05
2021
accepted:
21
10
2021
entrez:
13
11
2021
pubmed:
14
11
2021
medline:
5
4
2022
Statut:
epublish
Résumé
Parkinson's disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by α-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson's disease, but drug discovery is challenged by lack of in vivo models that recapitulate early stages of neurodegeneration. Invertebrate organisms, such as the nematode worm Caenorhabditis elegans, provide in vivo models of human disease processes that can be instrumental for initial pharmacological studies. To identify early motor impairment of animals expressing α-synuclein in dopaminergic neurons, we first used a custom-built tracking microscope that captures locomotion of single C. elegans with high spatial and temporal resolution. Next, we devised a method for semi-automated and blinded quantification of motor impairment for a population of simultaneously recorded animals with multi-worm tracking and custom image processing. We then used genetic and pharmacological methods to define the features of early motor dysfunction of α-synuclein-expressing C. elegans. Finally, we applied the C. elegans model to a drug repurposing screen by combining it with an artificial intelligence platform and cell culture system to identify small molecules that inhibit α-synuclein oligomers. Screen hits were validated using in vitro and in vivo mammalian models. We found a previously undescribed motor phenotype in transgenic α-synuclein C. elegans that correlates with mutant or wild-type α-synuclein protein levels and results from dopaminergic neuron dysfunction, but precedes neuronal loss. Together with artificial intelligence-driven in silico and in vitro screening, this C. elegans model identified five compounds that reduced motor dysfunction induced by α-synuclein. Three of these compounds also decreased α-synuclein oligomers in mammalian neurons, including rifabutin which has not been previously investigated for Parkinson's disease. We found that treatment with rifabutin reduced nigrostriatal dopaminergic neurodegeneration due to α-synuclein in a rat model. We identified a C. elegans locomotor abnormality due to dopaminergic neuron dysfunction that models early α-synuclein-mediated neurodegeneration. Our innovative approach applying this in vivo model to a multi-step drug repurposing screen, with artificial intelligence-driven in silico and in vitro methods, resulted in the discovery of at least one drug that may be repurposed as a disease-modifying therapy for Parkinson's disease.
Sections du résumé
BACKGROUND
Parkinson's disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by α-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson's disease, but drug discovery is challenged by lack of in vivo models that recapitulate early stages of neurodegeneration. Invertebrate organisms, such as the nematode worm Caenorhabditis elegans, provide in vivo models of human disease processes that can be instrumental for initial pharmacological studies.
METHODS
To identify early motor impairment of animals expressing α-synuclein in dopaminergic neurons, we first used a custom-built tracking microscope that captures locomotion of single C. elegans with high spatial and temporal resolution. Next, we devised a method for semi-automated and blinded quantification of motor impairment for a population of simultaneously recorded animals with multi-worm tracking and custom image processing. We then used genetic and pharmacological methods to define the features of early motor dysfunction of α-synuclein-expressing C. elegans. Finally, we applied the C. elegans model to a drug repurposing screen by combining it with an artificial intelligence platform and cell culture system to identify small molecules that inhibit α-synuclein oligomers. Screen hits were validated using in vitro and in vivo mammalian models.
RESULTS
We found a previously undescribed motor phenotype in transgenic α-synuclein C. elegans that correlates with mutant or wild-type α-synuclein protein levels and results from dopaminergic neuron dysfunction, but precedes neuronal loss. Together with artificial intelligence-driven in silico and in vitro screening, this C. elegans model identified five compounds that reduced motor dysfunction induced by α-synuclein. Three of these compounds also decreased α-synuclein oligomers in mammalian neurons, including rifabutin which has not been previously investigated for Parkinson's disease. We found that treatment with rifabutin reduced nigrostriatal dopaminergic neurodegeneration due to α-synuclein in a rat model.
CONCLUSIONS
We identified a C. elegans locomotor abnormality due to dopaminergic neuron dysfunction that models early α-synuclein-mediated neurodegeneration. Our innovative approach applying this in vivo model to a multi-step drug repurposing screen, with artificial intelligence-driven in silico and in vitro methods, resulted in the discovery of at least one drug that may be repurposed as a disease-modifying therapy for Parkinson's disease.
Identifiants
pubmed: 34772429
doi: 10.1186/s13024-021-00497-6
pii: 10.1186/s13024-021-00497-6
pmc: PMC8588601
doi:
Substances chimiques
alpha-Synuclein
0
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
77Subventions
Organisme : CIHR
ID : MC2-157081
Pays : Canada
Informations de copyright
© 2021. The Author(s).
Références
Cell Rep. 2019 Nov 26;29(9):2862-2874.e9
pubmed: 31775051
PLoS Genet. 2008 Mar 21;4(3):e1000027
pubmed: 18369446
Curr Neurol Neurosci Rep. 2017 Apr;17(4):31
pubmed: 28324300
Mol Neurodegener. 2010 Oct 28;5:43
pubmed: 21029459
Acta Neuropathol Commun. 2013 May 09;1:6
pubmed: 24252244
Autophagy. 2012 May 1;8(5):754-66
pubmed: 22647715
Autophagy. 2012 Jan;8(1):98-108
pubmed: 22113202
Acta Neuropathol. 2013 Jun;125(6):795-813
pubmed: 23604588
Curr Opin Neurol. 2003 Aug;16(4):443-9
pubmed: 12869801
Cell Metab. 2012 May 2;15(5):713-24
pubmed: 22560223
AIDS. 1990 May;4(5):433-41
pubmed: 2164820
J Neurosci. 2006 Oct 4;26(40):10082-90
pubmed: 17021164
Acta Neuropathol Commun. 2020 Feb 14;8(1):17
pubmed: 32059750
PLoS Comput Biol. 2008 Apr 25;4(4):e1000028
pubmed: 18389066
Acta Neurol Scand Suppl. 1984;100:49-54
pubmed: 6333134
Nat Methods. 2013 Sep;10(9):877-9
pubmed: 23852451
Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):E4708-15
pubmed: 27457957
Trends Neurosci. 2016 Nov;39(11):750-762
pubmed: 27776749
Nat Methods. 2011 Jun 05;8(7):592-8
pubmed: 21642964
J Neurosci. 2008 Jul 2;28(27):6926-37
pubmed: 18596167
J Neurochem. 2016 Dec;139(6):1163-1174
pubmed: 27731899
J Neurochem. 2015 Sep;134(5):943-55
pubmed: 26016728
PLoS One. 2008 Apr 02;3(4):e1867
pubmed: 18382657
Adv Drug Deliv Rev. 2014 Apr;69-70:247-53
pubmed: 24333896
Neurobiol Dis. 2015 Jul;79:81-99
pubmed: 25937088
PLoS One. 2010 Dec 10;5(12):e15360
pubmed: 21170329
NPJ Parkinsons Dis. 2015 Nov 19;1:15022
pubmed: 28725688
PLoS One. 2011 Feb 16;6(2):e14695
pubmed: 21358815
Mov Disord. 2018 May;33(5):678-683
pubmed: 29603370
J Biol. 2006;5(4):9
pubmed: 16725058
Nat Rev Neurosci. 2017 Sep;18(9):515-529
pubmed: 28747776
Acta Neuropathol Commun. 2021 Apr 7;9(1):62
pubmed: 33827706
Chembiochem. 2011 Mar 7;12(4):615-24
pubmed: 21271629
Nat Commun. 2018 Aug 27;9(1):3465
pubmed: 30150626
J Neurochem. 2004 Jan;88(2):337-48
pubmed: 14690522
Neurodegener Dis. 2004;1(4-5):175-83
pubmed: 16908987
Exp Gerontol. 2006 Sep;41(9):871-6
pubmed: 16782295
Nat Rev Drug Discov. 2019 Jan;18(1):41-58
pubmed: 30310233
Ann Neurol. 2015 Jan;77(1):15-32
pubmed: 25363075
Mol Neurodegener. 2015 Jul 11;10:26
pubmed: 26159606
JAMA Neurol. 2018 Jan 1;75(1):9-10
pubmed: 29131880
J Basic Clin Pharm. 2016 Mar;7(2):27-31
pubmed: 27057123
Lancet. 2015 Aug 29;386(9996):896-912
pubmed: 25904081
Biochem Biophys Res Commun. 2007 Nov 23;363(3):846-51
pubmed: 17900533
Neurosci Lett. 1994 Jul 4;175(1-2):114-6
pubmed: 7970190
Expert Opin Ther Targets. 2015 May;19(5):589-603
pubmed: 25785645
Sci Rep. 2017 Aug 8;7(1):7506
pubmed: 28790319
Pharmacoepidemiol Drug Saf. 2020 Aug;29(8):864-872
pubmed: 32410265
Proc Natl Acad Sci U S A. 2004 May 25;101(21):8084-9
pubmed: 15141086
FASEB J. 2011 Jan;25(1):326-36
pubmed: 20876215
Genetics. 1974 May;77(1):71-94
pubmed: 4366476
Neuropharmacology. 2014 Apr;79:249-61
pubmed: 24316465
Mov Disord. 2018 May;33(5):660-677
pubmed: 29644751
J Pharmacol Exp Ther. 2010 Mar;332(3):849-57
pubmed: 19934398
CNS Neurol Disord Drug Targets. 2012 Dec;11(8):965-75
pubmed: 23244416
Curr Protoc Mol Biol. 2010 Oct;Chapter 14:Unit14.20
pubmed: 20890901
J Biol Chem. 2006 Jan 6;281(1):334-40
pubmed: 16260788
Proc Natl Acad Sci U S A. 2013 May 7;110(19):E1817-26
pubmed: 23610405
Clin Ther. 2016 Apr;38(4):688-701
pubmed: 27130797
Front Mol Neurosci. 2017 Sep 27;10:311
pubmed: 29021741
Exp Neurol. 2017 Dec;298(Pt B):225-235
pubmed: 28987463
Acta Neuropathol. 2018 Feb;135(2):227-247
pubmed: 29134320
J Biol Chem. 2008 Jun 27;283(26):17962-8
pubmed: 18436529
PLoS One. 2008 May 21;3(5):e2208
pubmed: 18493300
J Vis Exp. 2021 Feb 2;(168):
pubmed: 33616088
Nat Neurosci. 2001 Oct;4(10):997-1005
pubmed: 11559854
EMBO J. 2009 Aug 19;28(16):2437-48
pubmed: 19609300
Mol Neurodegener. 2007 Jan 15;2:1
pubmed: 17224059
J Vis Exp. 2015 Jan 08;(95):52321
pubmed: 25591151
Science. 1993 Jul 30;261(5121):617-9
pubmed: 8342028
J Microsc. 1987 Sep;147(Pt 3):229-63
pubmed: 3430576
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
J Biomed Biotechnol. 2012;2012:845618
pubmed: 22536024
J Biol Chem. 2011 Aug 5;286(31):27081-91
pubmed: 21652708
Methods Mol Biol. 2011;793:129-48
pubmed: 21913098
EMBO Rep. 2002 Oct;3(10):962-6
pubmed: 12231504
J Neurosci. 2014 Dec 3;34(49):16518-32
pubmed: 25471588