CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.
Animals
Bridged-Ring Compounds
/ administration & dosage
Disease Models, Animal
Dopaminergic Neurons
/ drug effects
Humans
Male
Mice
Organophosphates
/ administration & dosage
Parkinson Disease
/ drug therapy
Protective Agents
/ administration & dosage
Protein Aggregates
/ drug effects
alpha-Synuclein
/ chemistry
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 09 2020
28 09 2020
Historique:
received:
09
05
2019
accepted:
27
08
2020
entrez:
28
9
2020
pubmed:
29
9
2020
medline:
23
10
2020
Statut:
epublish
Résumé
Parkinson's disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation.
Identifiants
pubmed: 32985503
doi: 10.1038/s41467-020-18689-x
pii: 10.1038/s41467-020-18689-x
pmc: PMC7522721
doi:
Substances chimiques
Bridged-Ring Compounds
0
CLR01 compound
0
Organophosphates
0
Protective Agents
0
Protein Aggregates
0
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4885Subventions
Organisme : Medical Research Council
ID : MR/N029453/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0700932
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-1504
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG050721
Pays : United States
Organisme : Parkinson's UK
ID : H-1003
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/1
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-0803
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-1103
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/J004324/1
Pays : United Kingdom
Organisme : Parkinson's UK
ID : J-0901
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-1305
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-0808
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K013866/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_MR/N50192X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M024962/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P007058/1
Pays : United Kingdom
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