Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 7; p. e2217835120
• Main Authors: Murray, Kevin A., Hu, Carolyn J., Pan, Hope, Lu, Jiahui, Abskharon, Romany, Bowler, Jeannette T., Rosenberg, Gregory M., Williams, Christopher K., Elezi, Gazmend, Balbirnie, Melinda, Faull, Kym F., Vinters, Harry V., Seidler, Paul M., Eisenberg, David S.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.02.2023
• Subjects: 60 APPLIED LIFE SCIENCES; Agglomeration; Aggregates; alpha-Synuclein - metabolism; Amyloid - metabolism; Animal tissues; Animals; Atrophy; Biocompatibility; Biological Sciences; Brain; Brain - metabolism; Caenorhabditis elegans - metabolism; Computational neuroscience; Cytotoxicity; Dismantling; Fibrils; Health services; Intracellular; Mice; Molecular dynamics; Movement disorders; Multiple System Atrophy - pathology; Neurodegenerative diseases; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Protein seeding; Synuclein; Synucleinopathies - pathology; Therapeutic targets; Toxicity; Parkinson's; disaggregation; amyloid; multiple system atrophy
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2217835120

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.