Amyloid Toxicity of Misfolded Amyloidogenic Peptides

Misfolding vs. Amyloid Diseases

The aggregation of proteins is normally tightly controlled,and misfolded proteins are generally removed by the proteosome before aggregation of the misfolded protein can occur. For reasons not clearly understood, in some individuals this degradation process breaks down and misfolded proteins accumulate in insoluble protein aggregates as time progresses. Out of the many proteins within the human genome, a small but growing number have been found to form the long, highly ordered β-sheet protein fibers that comprise amyloid deposits. A high percentage of these proteins have been linked to common and incurable disorders including Alzheimer’s, type II diabetes and Parkinson’s.

This link has led to an explosion of interest in amyloidogenic proteins. However, despite their prevalence in diseased tissue, most amyloid fibers are surprisingly inert. Instead of

mature fibers, small oligomers of amyloid proteins disrupt the cellular membranes and cause cell death. We are currently using a variety of biophysical techniques, including solution and solid-state NMR spectroscopy, to understand the folding/misfolding pathways of amyloid proteins and investigate compounds able to suppress the amyloid fibril formation and toxicity.

Interaction with membranes. To perform this task, we need to understand exactly how amyloid forming proteins kill cells. The toxicity of amyloid-forming proteins has been hypothesized to reside in the ability of protein oligomers to interact with and disrupt the cell membrane. Much of the evidence for this hypothesis comes from in vitro experiments using model membranes. Our goal is to shed light on the membrane

cell death

disruption process, studying the interaction of amyloidogenic protein with model membranes that more closely resemble the properties of biologic membranes. One idea is to vary the membrane lipid composition to understand how different kinds of membranes, e.g. plasma membrane, intracellular organelles' membrane, raft domain, etc. interact with and are affected by amyloidogenic proteins.

High resolution structure of protein monomers and aggregates. To date the structure of amyloidogenic proteins, especially small oligomers, which are believed to be the most toxic species, are largely unknown. This lack of information presents a problem in designing compounds designed to block amyloid-induced toxicity. Nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful techniques to study the structure of proteins and aggregates. Our interest is to develop and apply NMR spectroscopy to solve the structure of amyloidogenic proteins in different environments.

Role of metal ions in the fiber formation process. Homeostasis of metal ions is essential for the proper functioning of the cell. Since it is known that many metal ions can interact with amyloidogenic proteins, the dysregulation of metal ions could be one of the key points underlying the etiology of protein conformational diseases. Some metal ions inhibit the fiber formation process, but others seem to enhance the toxicity of amyloid. Our studies are focused on the nature of the interaction between metal ions and amyloid proteins, the structure of the protein-metal complex, as well as the role that several metals play in the fiber formation and/or membrane disruption process.

Inhibitors. There is a growing interest in studying natural compounds that inhibit the formation of fibrils and oligomers. The goal is to develop new drugs useful for preventing protein conformational diseases. Although several studies have shown the ability of some natural compounds to interfere with the formation of fibrils, to date the mechanisms underlying this behavior are not fully known. Our goal is to study and shed light on the mechanisms of interaction of various natural inhibitors, such as EGCG, resveratrol, curcumin, with amyloidogenic proteins.

Our publications on amyloid proteins