2. Academic Validation
  3. Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils

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

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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