Event

ChBE Seminar Series: Inchan Kwon

Tuesday, November 15, 2011
11:00 a.m.-12:15 p.m.
Room 2110 Chemical and Nuclear Engineering Bldg.
Professor Panagiotis Dimitrakopoulos
dimitrak@umd.edu

Modulation of Protein Aggregation Associated with Alzheimer's Disease and Other Neurodegenerative Diseases

Inchan Kwon
Assistant Professor
Department of Chemical Engineering
University of Virginia

Self-assembly of proteins play a key role in their diverse structure and functions as biocatalysts, nanobiomaterials, and protein drugs. However, undesirable structural change and aggregation of proteins are known to cause numerous neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease. AD is a debilitating and ultimately fatal disease. Currently, 5.3 million people are affected in the U.S., with the number projected to rise to 13.5 million by 2050. A hallmark of AD is the accumulation of neurotoxic amyloid-beta (Aβ) peptide aggregates. Growing evidence suggests that soluble Aβ aggregates are the primary toxic pathological species. Therefore, a promising therapeutic strategy to inhibit disease progression is the reduction of neurotoxic Aβ aggregates. Recently, we discovered that several small molecules with the demonstrated safety profiles significantly modulate Aβ aggregation and reduce Aβ-associated neurotoxicity. The small molecules were shown to reduce Aβ-associated cytotoxicity by generating non-toxic aggregates. We have also identified critical structural features of the small molecules for their modulating capabilities on Aβ aggregation and cytotoxicity through structure-function studies, which is expected to open new avenues into rational drug design for combating AD.

Intracellular aggregation of human copper, zinc superoxide dismutase (SOD1) mutants is implicated in ALS. In order to understand molecular mechanism of SOD1 aggregation, there is a need to develop a robust method that can accurately monitor aggregation of SOD1 mutant. Despites the benefits of mammalian cells to study aggregation of mutant SOD1s, mammalian cell-based monitoring methods have not been explored yet. In order to quantitatively and qualitatively monitor protein aggregation in mammalian cells, we established an in situ monitoring method utilizing a folding reporter GFP variant as a fusion partner. Our results signify that a folding reporter GFP fused to mutant SOD1 is a simple, but effective way to monitor mutant SOD1 aggregation in mammalian cells and also has a promise for a high-throughput screening for aggregation modulators.

Audience: Graduate  Post-Docs