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Cross-seeding at a molecular level: can amyloids breed?

ABG-100063 Stage master 2 / Ingénieur 6 mois stage gratifié
14/09/2021
CNRS UMR 5248, CBMN
Bordeaux Nouvelle Aquitaine France
  • Biochimie
  • Biologie
  • Biotechnologie

Établissement recruteur

This project is a collaboration between 3 teams of CBMN (Institute of Chemistry and Biology of Membranes and Nanoobjects, Bordeaux, France) (Cecile Feuillie (BioAFM team), Lucie Khemtemourian (SIMBA team) and Yann Fichou (NMR team)).

Description

Protein aggregation into amyloid fibrils is the hallmark of many diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) and type 2 diabetes (T2D). Amyloid fibrils contain a universal cross-βcore structure composed of arrays of β-sheets and can be formed by a variety of peptides or proteins without any evident sequence similarity. Different amyloid-based diseases are typically characterized by the aggregation of specific proteins. For instance, the tau protein is involved in AD, α-synuclein is involved in PD and the islet amyloid polypeptide (IAPP) plays an important role in T2D. Strikingly, cross-talks between aggregation of different proteins have been highlighted in various disease contexts [1]. As a hormone, IAPP enters the bloodstream to reach different targets, including the brain. In postmortem AD and PD patients, IAPP has been found in brain tissues alongside Tau and α-syn [2]. At a molecular level, this cross talk occurs through cross-seeding in which fibrils composed of one protein are capable of enhancing the aggregation of a different protein.

This project aims at studying cross-seeding between three proteins: tau, αSyn and IAPP. We endeavor to reveal the mechanisms underlying cross-seeding, e.g. primary or secondary nucleation, and to show whether or not structural features can be transferred through cross seeding.

We will first analyze aggregation kinetics of the three proteins alone and in the presence of seeds using Thioflavin T fluorescence. The data will be fitted according to previously established models [3], allowing to derive kinetic and thermodynamic parameters. We will then apply TEM, AFM and AFM-based infrared nanospectroscopy (nanoIR) to study aggregates morphology and structure of the obtained fibrils. All proteins are available in CBMN and the student will express tau or αSyn recombinantly in bacteria, depending on our stocks. Preliminary data obtained by a co-supervised M1 student show that pre-made aggregates of tau enhance aggregation of IAPP.

 

 

[1]  M. I. Ivanova, Y. Lin, Y. H. Lee, J. Zheng and A. Ramamoorthy, Biophys. Chem., 2021, 269, 106507.

[2]  I. Martinez-Valbuena, R. Valenti-Azcarate, I. Amat-Villegas, M. Riverol, I. Marcilla, C. E. de Andrea, J. A. Sánchez-Arias, M. del Mar Carmona-Abellan et al., Ann. Neurol., 2019, 86, 539–551.

[3]  G. Meisl, J. B. Kirkegaard, P. Arosio, T. C. T. Michaels, M. Vendruscolo, C. M. Dobson, S. Linse and T. P. J. Knowles, Nat. Protoc., 2016, 11, 252–272.

Profil

 

The candidate should be motivated and curious. He/she should have some background in biochemistry / biophysics / biotechnology and a real interest for learning new biophysical techniques. 

 

 

 

Prise de fonction

03/01/2022
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