Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 6, Pages E1009-E1017Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1610586114
Keywords
Parkinson's disease; protein aggregation; amyloid formation; toxic oligomers; drug development
Categories
Funding
- Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), US National Institutes of Health
- Boehringer Ingelheim Fonds
- European Research Council
- Cambridge Centre for Misfolding Diseases
- Agency for Science, Technology, and Research, Singapore
- BBSRC [BB/J002119/1] Funding Source: UKRI
- EPSRC [EP/K039520/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J002119/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/K039520/1] Funding Source: researchfish
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The self-assembly of alpha-synuclein is closely associated with Parkinson's disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects alpha-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces alpha-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of alpha-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing alpha-synuclein, observing a dramatic reduction of alpha-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson's disease and related conditions.
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