Protein diseases such as Alzheimer’s Disease (AD) and ALS are some of the most serious diseases leading to death in the Western world. Unsettled proteins play a major part in the course of the pathologic event for this disease family.
In AD, which also is the most common form of senile dementia, the pathologic development is due to the formation of millions of amyloid particles (plack) in the patients’ brain. Most of the plack consists of amyloid-b proteins (Ab). We will use a cross-disciplinary approach on Ab as a model system to characterize the fundamental differences between protein aggregation occurring on membrane surfaces and in solution.
Based on our recent work, we will use a range of biophysical methods centered around solid state NMR to provide the structural characterization of the aggregation process on membrane surfaces, and its temporal dependence on lipid composition and protein mutations. Correlating the structural information obtained for these membrane-mediated protein aggregates at different stages to their neurotoxic effects, will provide essential information about the mechanism and toxic impact of membrane-mediated Ab-aggregation. The methodological platform, developed with Ab, will then be used to study membrane-induced misfolding, aggregation and toxic consequences of Cu-Zn superoxide dismutase 1 (SOD). Here, initial results by us suggest that misfolding and aggregation of SOD on membrane surfaces plays a role in amyotrophic lateral sclerosis (ALS).
Together with a theoretical understanding of protein folding pathways on two-dimensional folding matrices, the generated structural and functional knowledge will be used to evaluate the importance of membrane-mediated aggregation in other amyloidogenic diseases.