Michael A. Myre, PhD, is researching the underlying pathogenic mechanisms that lead to the development of Huntington's Disease.
- Phone: 617-643-5536
Research Investigator Profile
Michael A. Myre, PhD
Harvard Medical School
- Assistant in Genetics,
Massachusetts General Hospital
My research is focused on elucidating the normal function of huntingtin. Huntingtin is a large HEAT repeat protein first identified in humans, where a polyglutamine tract expansion near the amino terminus causes a gain-of-function mechanism that leads to selective neuronal loss in Huntington’s disease (HD). The underlying pathogenic mechanisms that lead to the development of HD remain poorly understood as higher model organisms have revealed that huntingtin is an essential protein that is required for normal embryonic development in both the mouse and zebrafish, yet, is dispensable in the fly. Huntingtin is present throughout eukaryotic evolution except in fungi and plants and shows no close primary sequence homology to any other protein. Therefore, one approach to understand huntingtin function is to investigate its orthologs in tractable experimental lower organism models. To explore huntingtin function in both single cells and multicellular structures of the same organism, we have characterized a Dictyostelium ortholog (hd) of the human HD gene, generated a viable hd-null mutant and have delineated a number of consequent phenotypes. Dictyostelium is a bona fide multicellular eukaryotic organism with a haploid genome and relatively simple developmental program that serves as a model for basic biological research and is emerging as a valuable tool for understanding gene function for those genes known to cause disease in humans. We have found that in Dictyostelium, hd-deficient cells have a primary defect in the function of an organelle known as the contractile vacuole (CV), and as a consequence cells are hypersensitive to hypotonic conditions which negatively affects cAMP signal transduction pathways, and as a consequence development. We are currently exploring in greater detail, the biochemical defects that contribute to altered CV function in hd-deficient cells. By exploiting Dictyostelium as a model system, we expect to rapidly gain novel insight(s) into normal huntingtin function that ultimately, will enable specific validation studies in both mouse and human systems. Furthermore, insight into huntingtin normal function gained through studies using Dictyostelium will directly identify modifiers of signaling pathways that are altered by huntingtin deficiency. These modifiers then become prime targets of investigation in mammalian systems to explore potential huntingtin polyglutamine-length dependent effects that would implicate them as players in pathogenesis, and serve as possible routes towards a therapy.
|Research interests||Huntingtin normal function, presenilin normal function, signal transduction, development, Ca2+-calmodulin signaling, Dictyostelium discoideum biology, CLN3 normal function|
|Research techniques||Cellular and molecular biology, cell culture, live cell imaging, protein biochemistry, immunocytochemistry, use of Dictyostelium discoideum as a model organism, Systems biology, transcriptomics, proteomics, metabolomics|
|Diseases studied||Huntington’s Disease; neurodegenerative disorders, Alzheimer's disease, Batten's disease|
|NCBI PubMed link|
|Lab mailing address||Center for Human Genetic Research
Simches Research Center, CPZN-5.612A
185 Cambridge St.
Boston, MA 02114