Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils
- Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA 90095, HHMI, UCLA, Los Angeles, CA 90095
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095
- Pasarow Mass Spectrometry Laboratory, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089
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.
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- Grant/Contract Number:
- FC02-02ER63421
- OSTI ID:
- 1923941
- Alternate ID(s):
- OSTI ID: 2418850
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 7 Vol. 120; ISSN 0027-8424
- Publisher:
- Proceedings of the National Academy of SciencesCopyright Statement
- Country of Publication:
- United States
- Language:
- English