Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils.
Proc Natl Acad Sci U S A
; 120(7): e2217835120, 2023 02 14.
Article
en En
| MEDLINE
| ID: mdl-36757890
The amyloid aggregation of alpha-synuclein within the brain is associated with the pathogenesis of Parkinson's disease (PD) and other related synucleinopathies, including multiple system atrophy (MSA). Alpha-synuclein aggregates are a major therapeutic target for treatment of these diseases. We identify two small molecules capable of disassembling preformed alpha-synuclein fibrils. The compounds, termed CNS-11 and CNS-11g, disaggregate recombinant alpha-synuclein fibrils in vitro, prevent the intracellular seeded aggregation of alpha-synuclein fibrils, and mitigate alpha-synuclein fibril cytotoxicity in neuronal cells. Furthermore, we demonstrate that both compounds disassemble fibrils extracted from MSA patient brains and prevent their intracellular seeding. They also reduce in vivo alpha-synuclein aggregates in C. elegans. Both compounds also penetrate brain tissue in mice. A molecular dynamics-based computational model suggests the compounds may exert their disaggregating effects on the N terminus of the fibril core. These compounds appear to be promising therapeutic leads for targeting alpha-synuclein for the treatment of synucleinopathies.
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1
Banco de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Atrofia de Múltiples Sistemas
/
Sinucleinopatías
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2023
Tipo del documento:
Article