AREAS OF INVESTIGATION

The major research goal of our laboratory is to understand the molecular mechanisms that underlie neurodegenerative disorders associated with protein misfolding and aggregation, with a focus on Alzheimer’s disease (AD), Huntington’s disease (HD) and Parkinson’s disease (PD). In particular, we are interested in the potential role cellular and subcellular surfaces may play in these events.

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SIGNIFICANCE

There are a large and diverse number of diseases that are commonly classified as conformational diseases. The common feature of these diseases is the rearrangement of a specific protein to a non-native conformation that promotes aggregation and deposition within tissues and/or cellular compartments. Such diseases include Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), amyloidoses, the prion encephalopathies, and many more. A common structural motif in the majority of these diseases is the emergence of extended, β-sheet rich, proteinaceous fibrillar aggregates that are commonly referred to as amyloids. These fibrillar species are comprised of intertwined protofibrillar filaments, which often have globular, soluble protein aggregate precursors, more commonly referred to as oligomers. For the vast majority of these diseases, there are no widely effective preventative or therapeutic treatments.

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APPROACHES

We utilize a broad array of research tools and biochemical methods in our studies, but our primary tool is the atomic force microscope (AFM). AFM has provided particularly useful insights related to conformational disease due to its unique ability to be operated not only in air (ex situ) but also in solution (in situ), making it possible to directly visualize the behavior of biological macromolecules at solid-liquid interfaces, under nearly physiological conditions. The ultimate objective of our amyloidogenic peptide AFM studies is to elucidate the physiochemical aspects and molecular mechanisms of pathological self-assembly of biological macromolecules that lead to toxicity.

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QUESTIONS ADDRESSED IN ONGOING STUDIES

• What is the structural nature of abnormal protein conformations that trigger neurodegeneration?

• How do abnormal protein conformations mediate aberrant protein interactions that trigger neurodegeneration?

• What potential role does environment, especially surface chemistry, play in protein misfolding?

• How do specific point mutations in these peptides alter folding, aggregation, and toxicity?

• Are there specific interactions with lipids and lipid bilayers that play a role in toxicity, and how do these depend on the mechanical properties of a bilayer?

 

TECHNIQUE DEVELOPMENT

Due to the complex nature of these questions, we are also actively involved in further developing AFM techniques that will allow us to directly address these issues. Such techniques include methods to reconstruct tip-sample forces during tapping mode imaging in liquid environments. Such techniques would allow us to simultaneously collect morphological and mechanical information of biologically relevant peptides under near physiological conditions.