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

  • Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2217835120. doi: 10.1073/pnas.2217835120.
Kevin A Murray  1  2 ,  Carolyn J Hu  1  2 ,  Hope Pan  1  2 ,  Jiahui Lu  1  2 ,  Romany Abskharon  1  2 ,  Jeannette T Bowler  1  2 ,  Gregory M Rosenberg  1  2 ,  Christopher K Williams  3 ,  Gazmend Elezi  4 ,  Melinda Balbirnie  1  2 ,  Kym F Faull  4 ,  Harry V Vinters  3  5 ,  Paul M Seidler  6 ,  David S Eisenberg  1  2
Affiliations
  • 1. Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA 90095.
  • 2. HHMI, UCLA, Los Angeles, CA 90095.
  • 3. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095.
  • 4. Pasarow Mass Spectrometry Laboratory, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095.
  • 5. Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095.
  • 6. Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089.
PMID: 36757890 DOI: 10.1073/pnas.2217835120
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 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.

Keywords
Parkinson's; amyloid; disaggregation; multiple system atrophy.
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