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

AI Article Synopsis

  • - The accumulation of alpha-synuclein in the brain is linked to Parkinson's disease and related disorders, making it a key target for treatment.
  • - Researchers have discovered two small molecules, CNS-11 and CNS-11g, which can break down these harmful alpha-synuclein fibrils and reduce their toxicity in nerve cells.
  • - These compounds not only work on lab-generated fibrils but also disassemble those from patients with multiple system atrophy, showing potential as effective therapies for treating synucleinopathies and being able to target brain tissue in mice.

Article Abstract

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 . 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963379PMC
http://dx.doi.org/10.1073/pnas.2217835120DOI Listing

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