Master of Science
Department or Program
Department or Program Chair
Meredith Protas, PhD
Lisa M. Ellerby, PhD
Robert Barr, PhD
Huntington’s disease (HD) is an incurable genetic neurological disorder that affects 1 in 10,000 people, with no treatment that can alter the course of the disease. Neural cell death in the striatum and the cortex results from the accumulation of toxic mutant huntingtin protein (mHTT) fragments. Full length HTT is cleaved by proteases, including caspases, calpains and matrix metalloproteinases (MMPs). Previous research has also shown altered kinase signaling pathways in HD contribute to the localization of mutant huntingtin to the nucleus and to disruption of transcriptional regulation. Currently, there are no drugs that delay the onset or slow the progression of Huntington’s disease. We hypothesized that known drugs that target specific enzymes that have been evaluated in cancers and other neurological diseases may have therapeutic benefit in HD. Such enzymes that have been evaluated are MMP inhibitors and PCK activators, both enzymes that have been known to impact proteolytic processing and localization of mutant huntingtin. We evaluated these previously established compounds and their effect in HD mouse striatal cells, human neural stem cells, and transgenic mouse models. We have evaluated three MMP inhibitor compounds and found one that crosses the blood brain barrier and as predicted inhibits gelatinases. We have also found the PKC activator, Bryostain-1, increased the average life span in HD R6/2 treated mice.
Madushani, Kuruwitage, "Preclinical Evaluation of Matrix Metalloproteinase Inhibitors and Protein Kinase C Activators in Cell and Mouse Models of Huntington’s Disease" (2018). Master's Theses and Capstone Projects. 333.
Available for download on Monday, May 10, 2021