61281 20190709135451.0 doi 10.1073/pnas.1610586114 sideral 98209 ART-2017-98209 eng Perni, M. A natural product inhibits the initiation of a-synuclein aggregation & suppresses its toxicity 2017 Access copy available to the general public Unrestricted The self-Assembly of a-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 a-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 a-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 a-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 a-synuclein, observing a dramatic reduction of a-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. info:eu-repo/grantAgreement/ES/MINECO/RYC-2012-12068 info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 9.504 2017 MULTIDISCIPLINARY SCIENCES 5 / 64 = 0.078 2017 Q1 T1 6.092 2017 Multidisciplinary 2017 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Galvagnion, C. Maltsev, A. Meisl, G. Müller, M.B.D. Challa, P.K. Kirkegaard, J.B. Flagmeier, P. Cohen, S.I.A. Cascella, R. Chen, S.W. Limboker, R. Sormanni, P. Heller, G.T. Aprile, F.A. (orcid)0000-0002-9138-6687 Cremades, N. Universidad de Zaragoza Cecchi, C. Chiti, F. Nollen, E.A.A. Knowles, T.P.J. Vendruscolo, M. Bax, A. Zasloff, M. Dobson, C.M. 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 114, 6 (2017), E1009-E1017 Proc. Natl. Acad. Sci. Proceedings of the National Academy of Sciences 0027-8424 3085978 http://zaguan.unizar.es/record/61281/files/texto_completo.pdf Versión publicada 40560 http://zaguan.unizar.es/record/61281/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:61281 articulos driver 2019-07-09-11:40:44 ARTICLE