Reduction of SOD Aggregation Using In Vitro and In Vivo ALS Models

ALS;ube4b;Biochemistry

Shea, JohnWang, Jiou ;

Johns Hopkins University

关键词: ALS;    ube4b;    Biochemistry;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60328/SHEA-THESIS-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Many neurodegenerative diseases are characterized by the presence of misfolded proteins and proteotoxicity. While the dysfunctional proteins may differ from disease to disease, the resultant neuronal stress can create debilitating cognitive and motor deficits. In our lab, we are working toward ways to reduce these symptoms in Amyotrophic Lateral Sclerosis (ALS) through experiments on cell, mouse, and in vitro models. Two efforts were used to reduce the proteotoxicity resulting from aggregation of a mutated superoxide dismutase (SOD1): screening for a UBE4B inhibitor and treatment with an inhibitor of Heat Shock Protein 90 (HSP90). An assay able to model UBE4B auto-ubiquitination in vitro was found to be reliable, scalable, and useful for finding potential inhibitors of UBE4B. Meanwhile, cellular exposure to the HSP90 inhibitor, NVP-BEP 800, was shown to reduce SOD aggregation, but a drug trial in mice did not show significant results. The UBE4B assay and mouse drug injection results have provided valuable information for optimizing future experiments, with the assay in particular showing unique potential.