An enzyme linked to a neurodevelopmental disorder has been found to play an important role in digesting viral proteins during infection, UT Southwestern researchers report.

The research, published in the Journal of Clinical Investigation, is a continuation of the work of the late Beth Levine, M.D., who was Director of the former Center for Autophagy Research at UTSW and a pioneer in the field of autophagy, the natural process of cellular recycling.

“This project was birthed in her lab,” said Josephine Thinwa, M.D., Ph.D., lead author of the study. “We’re trying to answer questions that go beyond viral infection.”

Dr. Thinwa’s autophagy research began when she was a postdoc in the lab of the late Beth Levine, M.D., who once directed UT Southwestern’s former Center for Autophagy Research. Dr. Levine was a pioneer in this field, and today Dr. Thinwa is honored to carry on her mentor’s work in the scientific specialty. Photo courtesy of the Infectious Diseases Society of America.

Dr. Thinwa, now an Assistant Professor of Internal Medicine and Microbiology, was a postdoctoral fellow in Dr. Levine’s lab when she started the project. Dr. Levine’s team had identified about 200 genes linked to virus-induced autophagy – a process by which cells clear out damaged cellular components or destroy invasive pathogens like viruses.

One of the genes coded for a protein called CDKL5, which caught Dr. Thinwa’s attention because little was known about it, except that mutations of the CDKL5 gene cause a rare neurodevelopmental disorder that includes seizures, muscle dysfunction, cognitive impairment, and other symptoms. At the time, CDKL5 had no known link to autophagy.

“If we could discover its role in autophagy, we could also find out why it’s so important in neurodevelopment,” Dr. Thinwa said. With that connection in mind, she proposed further study to Dr. Levine.

Dr. Levine was rigorous about approving research proposals, Dr. Thinwa said, so it was exciting to get a greenlight for the project.

After Dr. Levine’s death, Dr. Thinwa continued her investigation under the leadership of several faculty members, including Michael Shiloh, M.D., Ph.D., Associate Professor of Internal Medicine and Microbiology, and Tiffany Reese, Ph.D., Assistant Professor of Immunology and Microbiology.

Dr. Thinwa, whose lab is in the space previously occupied by the Center that Dr. Levine once oversaw, is now looking into how CDKL5 influences brain development and helps cells in the brain resist viral infection.

“It was team science, a great example of collegiality here at UT Southwestern,” Dr. Thinwa said. “We had the main fundamentals before Beth died, and then I worked on the mechanisms.”

Key findings of the research by Dr. Thinwa and her colleagues include:

• CDKL5 modifies a protein called p62, which is known to be part of the autophagy mechanism, by transferring a phosphate group to p62 (a process called phosphorylation).
• In cultured human and mouse cells and in mice, deleting the CDKL5 gene makes cells more vulnerable to attack by several viruses and makes animals more susceptible to disease.
• Deleting the CDKL5 gene also increases the number of viral capsids in a cell. Capsids are the external shells that protect the genetic material of a virus.

“The take-home message is that Dr. Thinwa has identified a very early point in virus-related autophagy,” Dr. Shiloh said.

Dr. Thinwa, whose lab is in the space previously occupied by the Center that Dr. Levine once oversaw, is now looking into how CDKL5 influences brain development and helps cells in the brain resist viral infection.

“We found very provocative data that CDKL5 protects cells during infection, and if it’s knocked out, cell death increases. The beauty of autophagy is it’s so interconnected with all parts of our cells,” she said. “I’m very proud of carrying on the work of Beth Levine in the same lab space.”