Seeded Protein Aggregation and Disease

Protein misfolding, aggregation and amyloid fibril formation processes are associated with a large group of diseases such as Alzheimer´s disease and Creutzfeldt-Jakob disease.

Amyloid fibril formation is accelerated in the presence of pre-formed fibril seeds that circumvent the nucleation dependent step of the reaction.

It is known that many factors can influence this molecular process, but initation, propagation, and tissue response in vivo are uncharted territory.

The proposed work will answer questions on conformational diversity of amyloidogenic proteins and how it influences seeding, cross-seeding, chaperoning mechanisms, amyloid degradation, and tissue specificity of pathology.

It is rather unknown how misfolded proteins induce cascades of detrimental processes, but we have made substantial progress over the past years.

We here propose continued work using molecular biophysics, structural studies, disease models and tissues researching four canonical proteins aggregating in human degenerative diseases (Aβ, Tau, prion protein, and transthyretin).

We study how these proteins cross-interact, affect biological processes, and how misfolding can be influenced by exogenous seeds from e.g. iatrogenic interventions such as protein based drugs with inherent amyloidogenic properties.

Our final goals are to facilitate disease risk awareness, and contribute to molecular diagnostics and therapeutics of amyloid diseases.