Molecular studies of ALS by in-cell NMR


Project leader


Funding source

Swedish Foundation for Strategic Research - Stiftelsen för strategisk forskning


Project Details

Start date: 01/05/2011
End date: 30/04/2014
Funding: 2100000 SEK


Description

How the crowded and highly complex environment inside living cells - bursting of molecular activities and housekeeping systems - modulates protein structure and function pose a continuous challenge to experimental science. At the same, disturbances of the very interplay between the cellular interior and some proteins have arisen as the key determinant in development of our most common aging diseases, most strikingly in protein-misfolding diseases like Alzheimer's disease, Parkinson's disease and ALS. In a collaborative effort between specialist groups in Japan and Sweden, we have recently been able to obtain atomic-resolution NMR data from the ALS-associated protein Cu/Zn superoxide dismutase (SOD1) inside cultured human cells. The data show that the dynamic behaviour of the SOD1 scaffold inside the living cells is distinctly different from that in vitro - we have a tool to measure, for the first time, the molecular interplay between the cellular interior and a disease-associated protein. The second phase of the project will examine in more detail how the properties of the SOD1 structure are modulated by the intra-cellular milieu and, most critically, the pathway for pathological misfolding and aggregation in vivo. An important component of the latter analysis will be the transfer of ALS-associated SOD1 mutants into neural cells, derived from fibroblast of patients with matching genetic background of the disease.

Last updated on 2017-29-03 at 17:13