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.
","abstract_html":"<p>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.</p>","abstract_has_math":false,"creators":["Madushani, Kuruwitage"],"institution":null,"degree_name":"Master of Science","degree_level":"Master's Thesis","degree_discipline":"Biological Sciences","degree_department":null,"school":null,"contributors":["Lisa M. Ellerby, PhD","Robert Barr, PhD","Meredith Protas, PhD"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-05-01T07:00:00Z","date_published":"2018-05-01T07:00:00Z","updated_at":"2026-07-24T02:04:51Z","subjects":["Huntington's Disease","Mutant Huntingtin","Matrix Metalloproteinase","Inhibitors","Neurodegeneration","Gelatinases","Protein Kinase C","Enzymes","Neuroscience and Neurobiology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://scholar.dominican.edu/masters-theses/333","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Lisa M. Ellerby, PhD","Robert Barr, PhD","Meredith Protas, PhD"]},{"key":"dc:creator","label":"Author","values":["Madushani, Kuruwitage"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2022-05-31T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biological Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Master's Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Huntington's Disease","Mutant Huntingtin","Matrix Metalloproteinase","Inhibitors","Neurodegeneration","Gelatinases","Protein Kinase C","Enzymes","Neuroscience and Neurobiology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholar.dominican.edu/masters-theses/333"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["Preclinical Evaluation of Matrix Metalloproteinase Inhibitors and Protein Kinase C Activators in Cell and Mouse Models of Huntington’s Disease"]}]}],"canonical_facts":{"dc:contributor":["Lisa M. Ellerby, PhD","Robert Barr, PhD","Meredith Protas, PhD"],"dc:creator":["Madushani, Kuruwitage"],"dc:date.available":["2022-05-31T07:00:00Z"],"dc:description.abstract":["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.
"],"dc:identifier":["https://scholar.dominican.edu/masters-theses/333"],"dc:subject":["Huntington's Disease","Mutant Huntingtin","Matrix Metalloproteinase","Inhibitors","Neurodegeneration","Gelatinases","Protein Kinase C","Enzymes","Neuroscience and Neurobiology"],"dc:title":["Preclinical Evaluation of Matrix Metalloproteinase Inhibitors and Protein Kinase C Activators in Cell and Mouse Models of Huntington’s Disease"],"thesis:degree_discipline":["Biological Sciences"],"thesis:degree_level":["Master's Thesis"],"thesis:degree_name":["Master of Science"]},"updated_at":"2026-07-24T02:04:51Z"}