Respiratory infections peak during the winter months, and most people recover within a few weeks. But for those with a rare genetic lung disease, the sniffling, coughing and congestion never end. The tiny hairlike structures called cilia that normally sweep mucus through the airways don’t work properly in people with what’s known as primary ciliary dyskinesia. When the cilia don’t brush microbes away, it is hard to clear an infection and easy to get another one.
Most people with this disease carry mutations in one of the genes that build the proteins that form molecular motors inside cilia. A single misshapen piece of protein can make the whole machine grind to a halt. But a few people have errors in proteins that are not part of the motor. Until now, no one understood why their cilia don’t beat.
1986 University alumnus Michael Yarbrough, manager of community outreach and player involvement with the St. Louis Rams, chats with students (from left) Amy Katz, Kate Gerber and Erica Sampson during a recent networking reception sponsored by The Career Center. The reception allowed current students to meet with alumni and discuss job searching and career opportunities.
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With the help of David Piston, PhD, the Edward Mallinckrodt Jr. Professor and head of the Department of Cell Biology and Physiology, and staff scientist Alessandro Ustione, PhD, the researchers showed that the three proteins form a scaffold on which the molecular motor later is to be built.
Horani swabbed the noses of some of his patients and grew ciliated cells from them. He found that the scaffold is constructed incorrectly in cells with mutations in any of the three early genes. The proteins that comprise the motor arrive at the faulty scaffolding, but rather than passing through an efficient assembly line and forming a motor, they collect haphazardly into a heap.
“Piling together misfolded proteins turns out to be the way that the body tries to get rid of abnormal proteins,” Horani said. “Now that we know what is wrong, we want to find out, ‘How can we make this work?’ We’re starting to study whether we can prevent the protein heaps from forming and somehow rescue the parts of the motors. If we can get just a few of these proteins to assemble, we may be able to improve quality of life for people with this disease.”
Horani A, Ustione A, Huang T, Firth AL, Pan J, Gunsten SP, Haspel JA, Piston DW, Brody SL. Establishment of the early cilia preassembly protein complex during motile ciliogenesis. Proceedings of the National Academy of Sciences. Jan. 22, 2018.
This work was funded by the American Thoracic Society Foundation/Primary Ciliary Dyskinesia Foundation/Kovler Family Foundation; the National Institutes of Health (NIH), grant number HL128370; the Washington University Center for Cellular Imaging through The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital, grant number CDI-CORE-2015-505; and the Foundation for Barnes-Jewish Hospital, grant number 3770.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
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