The molecular tweezer CLR01 inhibits aberrant superoxide dismutase 1 (SOD1) self-assembly
Amino Acid Sequence
Amyotrophic Lateral Sclerosis
/ genetics
Animals
Binding Sites
Body Weight
/ drug effects
Bridged-Ring Compounds
/ metabolism
Disease Models, Animal
Mice
Muscle Strength
/ drug effects
Mutation
Organophosphates
/ metabolism
Protein Aggregates
/ drug effects
Spinal Cord
/ drug effects
Superoxide Dismutase-1
/ chemistry
Survival Analysis
amyloid
amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)
inhibitor
molecular tweezer
motor neuron
mouse
neurodegeneration
protein aggregation
protein misfolding
superoxide dismutase (SOD)
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
08 03 2019
08 03 2019
Historique:
received:
20
09
2018
revised:
01
01
2019
pmc-release:
08
03
2020
pubmed:
4
1
2019
medline:
21
5
2019
entrez:
4
1
2019
Statut:
ppublish
Résumé
Mutations in superoxide dismutase 1 (SOD1) cause 15-20% of familial amyotrophic lateral sclerosis (fALS) cases. The resulting amino acid substitutions destabilize SOD1's protein structure, leading to its self-assembly into neurotoxic oligomers and aggregates, a process hypothesized to cause the characteristic motor-neuron degeneration in affected individuals. Currently, effective disease-modifying therapy is not available for ALS. Molecular tweezers prevent formation of toxic protein assemblies, yet their protective action has not been tested previously on SOD1 or in the context of ALS. Here, we tested the molecular tweezer CLR01-a broad-spectrum inhibitor of the self-assembly and toxicity of amyloid proteins-as a potential therapeutic agent for ALS. Using recombinant WT and mutant SOD1, we found that CLR01 inhibited the aggregation of all tested SOD1 forms
Identifiants
pubmed: 30602569
pii: S0021-9258(20)38979-1
doi: 10.1074/jbc.RA118.005940
pmc: PMC6416427
doi:
Substances chimiques
Bridged-Ring Compounds
0
CLR01 compound
0
Organophosphates
0
Protein Aggregates
0
Superoxide Dismutase-1
EC 1.15.1.1
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
3501-3513Subventions
Organisme : NINDS NIH HHS
ID : F32 NS087858
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR057230
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM103479
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR028893
Pays : United States
Informations de copyright
© 2019 Malik et al.
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