A natural product inhibits the initiation of a-synuclein aggregation & suppresses its toxicity

Perni, M. ; 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. ; 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.

Resumen: 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.

Idioma: Inglés

DOI: 10.1073/pnas.1610586114

Año: 2017

Publicado en: Proceedings of the National Academy of Sciences 114, 6 (2017), E1009-E1017
ISSN: 0027-8424

Factor impacto JCR: 9.504 (2017)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 5 / 64 = 0.078 (2017) - Q1 - T1

Factor impacto SCIMAGO: 6.092 - Multidisciplinary (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MINECO/RYC-2012-12068

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)