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Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism.
Limbocker, Ryan; Mannini, Benedetta; Ruggeri, Francesco S; Cascella, Roberta; Xu, Catherine K; Perni, Michele; Chia, Sean; Chen, Serene W; Habchi, Johnny; Bigi, Alessandra; Kreiser, Ryan P; Wright, Aidan K; Albright, J Alex; Kartanas, Tadas; Kumita, Janet R; Cremades, Nunilo; Zasloff, Michael; Cecchi, Cristina; Knowles, Tuomas P J; Chiti, Fabrizio; Vendruscolo, Michele; Dobson, Christopher M.
Afiliación
  • Limbocker R; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Mannini B; Department of Chemistry and Life Science, United States Military Academy, West Point, NY, 10996, USA.
  • Ruggeri FS; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Cascella R; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Xu CK; Department of Experimental and Clinical Biomedical Science, University of Florence, 50134, Florence, Italy.
  • Perni M; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Chia S; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Chen SW; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Habchi J; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Bigi A; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Kreiser RP; Department of Experimental and Clinical Biomedical Science, University of Florence, 50134, Florence, Italy.
  • Wright AK; Department of Chemistry and Life Science, United States Military Academy, West Point, NY, 10996, USA.
  • Albright JA; Department of Chemistry and Life Science, United States Military Academy, West Point, NY, 10996, USA.
  • Kartanas T; Department of Chemistry and Life Science, United States Military Academy, West Point, NY, 10996, USA.
  • Kumita JR; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Cremades N; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Zasloff M; Institute for Biocomputation and Physics of Complex Systems (BIFI)-Joint Unit BIFI-IQFR (CSIC), University of Zaragoza, 50018, Zaragoza, Spain.
  • Cecchi C; MedStar-Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC, 20010, USA.
  • Knowles TPJ; Department of Experimental and Clinical Biomedical Science, University of Florence, 50134, Florence, Italy.
  • Chiti F; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
  • Vendruscolo M; Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, CB3 0HE, UK.
  • Dobson CM; Department of Experimental and Clinical Biomedical Science, University of Florence, 50134, Florence, Italy. fabrizio.chiti@unifi.it.
Commun Biol ; 3(1): 435, 2020 08 13.
Article en En | MEDLINE | ID: mdl-32792544
The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-ß (Aß) in Alzheimer's disease and α-synuclein (αS) in Parkinson's disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of αS, Aß and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Espermina / Membrana Celular / Colestanos / Pliegue de Proteína / Multimerización de Proteína Límite: Humans Idioma: En Revista: Commun Biol Año: 2020 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Espermina / Membrana Celular / Colestanos / Pliegue de Proteína / Multimerización de Proteína Límite: Humans Idioma: En Revista: Commun Biol Año: 2020 Tipo del documento: Article Pais de publicación: Reino Unido