New Research Could Lead to Greater Understanding of Myosin II-Related Diseases

A new paper by Karen Kasza, Clare Boothe Luce Assistant Professor of Mechanical Engineering at Columbia University, reveals new research observing the effects of mutations in myosin (motor proteins that help generate forces required for cell movement) on the behaviors of proteins, cells, and tissues in an organism. Kasza and her team examined myosin protein mutations in fruit flies, which could lead to better understanding of myosin-II-related diseases in humans.

"By 'watching' how cells move and generate forces inside living tissues, we've uncovered new clues as to why mutations in the MYH9 gene cause a broad spectrum of disorders in humans." Kasza observes. "Our work sheds new light on how motor proteins generate forces inside living tissues and on how genetic factors alter these forces to result in disease. This mechanistic understanding will help us better understand these diseases and could lead to new diagnostic or therapeutic strategies down the road."

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Myosins are motor proteins that convert chemical energy into mechanical work, generating force and movement. Myosin II generates forces that are essential to drive cell movements and cell shape changes that generate tissue structure. While researchers know that mutations in the genes that encode nonmuscle myosin II lead to diseases, including severe congenital defects as well as blood platelet dysfunction, nephritis, and deafness in adults, they do not fully understand the mechanisms that translate altered myosin activity into specific changes in tissue organization and physiology.

A team of researchers led by Karen Kasza, Clare Boothe Luce Assistant Professor of Mechanical Engineering, used the Drosophila embryo to model human disease mutations that affect myosin motor activity. Through in vivo imaging and biophysical analysis, they demonstrated that engineering human MYH9-related disease mutations into Drosophila myosin II produces motors with altered organization and dynamics that fail to drive rapid cell movements, resulting in defects in epithelial morphogenesis. The study—the first to demonstrate that these mutations result in slower cell movements in vivo—was published October 15, 2019, by PNAS.

"It's not currently possible to watch what happens at the cell level when these genes are mutated in humans, and it's still really difficult to do this in mammalian model organisms like mice," says Kasza, the study's lead author who began the research as a postdoctoral fellow at the Sloan Kettering Institute and continued it when she joined Columbia Engineering in 2016.

Because there are so many similarities between the myosin II protein in humans and in fruit flies, Kasza's approach was to start by tackling how to "watch" the effects of myosin II mutations in fruit flies. Her group engineered the human disease mutations into fruit fly myosin and then observed how this affected the behaviors of the proteins, cells, and tissues in the organism.

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