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Molecular basis of the early events triggering protein diseases

 

Challenge: Neurodegeneration

Libros blancos:

  • Structural bases of life and evolution of macromolecular complexity (Challenge 2; CSIC white book vol. 2) 
  • Understanding mental disorders (Challenge 6; CSIC white book vol. 5)
  • Aging & brain degeneration (Challenge 7; CSIC white book vol. 5)

PI: Javier Oroz

     

Although the critical toxic species in over 40 human diseases are misfolded proteins, we still lack a mechanistic understanding of the early structural changes in amyloid proteins that prompt their toxicity, aggregation and cell death. We study the structural basis of the gain-of-toxic action that determine protein pathologies involving TDP-43 and FUS, which are critical in the development of Amyotrophic Lateral Sclerosis. Using state-of-the art NMR and gene-editing techniques, we also describe the mechanisms used by molecular chaperones to modulate protein diseases.

resline jo

In the image, structure of the pro-toxic complex formed by Hsp90-FKBP51 and Tau proteins.

Publications

Oroz J, Chang BJ, Wysoczanski P, Lee CT, Pérez-Lara A, Chakraborty P, Hofele R, Baker JD, Blair LJ, Biernat J, Urlaub H, Mandelkow E, Dickey CA, Zweckstetter M (2018). Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex. Nature Communications. 9 (1): 4532.

Mok SA, Condello C, Freilich R, Gillies A, Arhar T, Oroz J, Kadavath H, Julien O, Assimon VA, Rauch JN, Dunyak BM, Lee J, Tsai FTF, Wilson MR, Zweckstetter M, Dickey CA, Gestwicki JE (2018) Mapping interactions with the chaperone network reveals factors that protect against tau aggregation. Nat. Struct. Mol. Biol. 25 (5): 384-393.

Oroz, J., Kim JH, Chang BJ, Zweckstetter M (2017) Mechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90. Nat. Struct. Mol. Biol. 24 (4): 407-13.

Collaborators

  • Alberto García Redondo (Hospital 12 de Octubre Hospital)
  • María Gasset (IQFR)
  • Abraham Acevedo (Hospital Universitario de Canarias)
  • Eurico Cabrita (Nova School of Science & Technology, Lisbon)
  • Kausik Si (Stowers Institute, US)
  • Rubén Herás (University of Hong Kong)

Financing

  • Leonardo Grant FBBVA(30/09/2019-31/03/2021)      
  • Retos MICINN/AEI 2019 (01/06/2020-31/05/20023)  
  •   Ramón y Cajal 2018 (01/01/2020-26/03/2025)