| Literature DB >> 28096355 |
Michele Perni1,2, Céline Galvagnion1, Alexander Maltsev3, Georg Meisl1, Martin B D Müller1,2, Pavan K Challa1, Julius B Kirkegaard4, Patrick Flagmeier1, Samuel I A Cohen1, Roberta Cascella5, Serene W Chen1, Ryan Limbocker1, Pietro Sormanni1, Gabriella T Heller1, Francesco A Aprile1, Nunilo Cremades6, Cristina Cecchi5, Fabrizio Chiti5, Ellen A A Nollen2, Tuomas P J Knowles1, Michele Vendruscolo7, Adriaan Bax8, Michael Zasloff9, Christopher M Dobson7.
Abstract
The self-assembly of α-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 α-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 α-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 α-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 α-synuclein, observing a dramatic reduction of α-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.Entities:
Keywords: Parkinson’s disease; amyloid formation; drug development; protein aggregation; toxic oligomers
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Year: 2017 PMID： 28096355 PMCID： PMC5307473 DOI： 10.1073/pnas.1610586114
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205