CI2Daggett Research Group | Research | Unfolding Diseases

University of Washington - College of Engineering - School of Medicine - Department of Bioengineering

Selected Projects

Disease-Related
Proteins & Petides

Aβ Peptide
β2-Microglobulin
Lysozyme
Polyglutamine
Superoxide Dismutase
Transthyretin
Projects
Conversion Pathways
Misfolded Intermediates
Modeling of Toxic Aggregates

Unfolding Diseases

Several neurodegenerative diseases are related to the misfolding and aggregation of specific proteins, for example Alzheimer's disease, Parkinson's disease and Huntington's disease. Each protein is related to one or more unique diseases, but the protein aggregates seem to share a common structure: insoluble fibrils with β-sheets running parallel to the axis (amyloid). Recent advances however indicate that the toxic particles are probably soluble oligomers, either prefibrillar aggregates or unrelated species. Detailed mechanisms of misfolding and structures of toxic aggregates are yet unknown and difficult to discern through experimental methods.

SOD1

The Daggett lab studies the early stages of the misfolding and aggregation of the disease-related proteins through molecular dynamics simulations under misfolding conditions. We have previously studied Alzheimer's Aβ peptide, Huntington's polyQ repeats, transthyretin, lysozyme, and β2-microglobulin. Currently, we mostly focus on superoxide dismutase (SOD1) -- related to Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's Disease. We also perform extensive studies on the Prion protein, which is related to several misfolding diseases.

Our studies on SOD1 first focused on one of the most common heritable ALS mutations, a change from alanine to valine at the fourth amino acid (A4V). Simulations indicated that introduction of this mutation causes a loss of residue contacts resulting in destabilization of the dimer and metal-binding sites and a gain of residue contacts that lead to misfolding. Based on this research we have expanded our simulations to other ALS-associated mutations in order to find common features of the mutant forms that may increase their propensity for aggregation.

The knowledge gained on the mechanisms of misfolding and aggregation can be exploited to design markers and inhibitors for disease, another area of active reasearch in the lab.

Relevant Publications