Are all Protein Aggregates Toxic?

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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. Aβ42 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 Aβ42 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 Aβ42 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.