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14 december 2018

Approved FOM programme

Number 127.
Title A single-molecule view on protein aggregation (SMPA) 
Executive organisational unit BUW
Programme management Prof.dr. V. Subramaniam
Duration 2011-2015
Cost estimate M€ 2.5

This programme aims to apply an array of innovative single-molecule techniques, augmented by selected ensemble and computational biophysics approaches, to yield an unprecedented molecular and dynamic view on protein aggregation. We will bridge molecular and cellular perspectives with well-controlled in vitro experiments complemented by innovative single molecule and super-resolution methods to follow aggregation interactions within cells. 

Background, relevance and implementation
Understanding protein nucleation and aggregation is one of the major challenges in contem­porary biophysics and, in the context of disease, one with great medical relevance. The ambi­tion of this programme is to unravel the physical mechanisms that underlie the dynamics of nucleation and formation of early aggregate species. At the core of the programme is the physics of protein folding, conformational dynamics and protein-protein and protein-membrane interactions.

Protein misfolding and aggregation lies at the heart of a range of devastating diseases, inclu­ding neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The underlying physics is poorly understood, and has broader significance, including in the assembly of food proteins to provide texture, supramolecular assembly of proteins to form functional com­plexes, and biologically templated formation of novel materials.

Ensemble biophysics approaches are not well suited to capture the dynamics and structural changes associated with individual folding and binding transitions, which are critical to a mechanistic understanding of the earliest steps in protein aggregation. The transient nature, inherent heterogeneity, and low numbers of early stage aggregates necessitate single molecule spectroscopy approaches and other innovative methods that can detect distributions of struc­tures in ensembles. We will investigate the physical mechanisms underlying the dynamics of nucleation and formation of early aggregate species of human α-synuclein, focusing on three key questions:
1. How do multiple α-synucleins aggregate?
2. How do early aggregates perturb phospholipid membranes?
3. What are the cellular and genetic triggers of aggregation?

The programme consortium will use state of the art experimental and computational biophysics approaches, complemented by methods from protein chemistry and molecular biology and genetics of neurodegenerative disease to unravel the knotty problem of protein aggregation.

The final evaluation of this programme will consist of a self-evaluation initiated by the programme leader and is foreseen for 2016.

Please find a research highlight that was achieved in 2014 within this FOM programme here.