PROJECT SUMMARY
Abnormal aggregation and deposition of misfolded proteins have been recognized as a common pathological
hallmark of several neurodegenerative diseases. The goal of this project is to identify unique physicochemical
properties of aggregates, shared by a large number of structurally diverse proteins (e.g. Aß42 peptide, insulin
and lysozyme), that are toxic. In general, the scientific community agrees that soluble aggregates of proteins,
especially those that are in the form of proto-fibrils, are noxious. These aggregates can cause toxicity by
several mechanisms such as, aberrant interaction with cellular membranes, organelles, interaction with other
proteins that may be critical for cellular functions, or by clogging the protein degradation and clearing
pathways. However, there is paucity in literature showing a clear correlation between aggregated proteins
shape (e.g. amorphous, globular, or fibril), flexibility (e.g. flexible, or rigid), size (e.g. monomer, oligomer, or
fibril), and hydrophobicity, with its associated toxicity. Our findings on Aß42 peptide aggregation and toxicity
shows that increased surface hydrophobicity of protein aggregates can contribute to an increase in cellular
toxicity. We hypothesize that flexible protein aggregates with increased surface hydrophobicity may hold the
key to cellular toxicity. To test this hypothesis, we will use simple but unrelated proteins (e.g. insulin and
lysozyme) which are normally not toxic and compare the properties of the aggregates of these proteins with
Aß42 peptide aggregates whose role in Alzheimer’s disease is well known. We will generate diverse
aggregated structures from these proteins, characterize their biochemical and biophysical properties including
size, shape, flexibility, relative hydrophobicity, and measure their associated toxicity. This will also help us
address: “Is it the sequence or the unique physicochemical properties of the aggregated protein that is critical
for its toxicity”. As a result, it will help us identify key physicochemical properties shared by protein aggregates
that are central to their toxicity.