Skip to main content

Protein ‘clumping’ linked to severe form of genetic epilepsy

Aug. 13, 2015, 9:09 AM

Robert Macdonald, M.D., Ph.D., Jing-Qiong Kang, M.D., Ph.D., and colleagues have demonstrated that aggregation of abnormal proteins can contribute to a severe form of genetic epilepsy. (photo by Susan Urmy)

Researchers at Vanderbilt University for the first time have demonstrated in a mouse model that aggregation, the “clumping together” of abnormal proteins, can contribute to a severe form of genetic epilepsy.

Their findings, reported recently in the journal Nature Neuroscience, challenge conventional wisdom that abnormal seizure activity alone is responsible for the developmental delay, severe cognitive impairment and sudden death associated with catastrophic epilepsies such as Dravet syndrome.

The discovery “was a quite a shock to us, to the whole field of neuroscience, probably, because no one had ever thought a genetic epilepsy associated with ion channel mutation had a protein aggregate,” said first and corresponding author Jing-Qiong Kang, M.D., Ph.D., assistant professor of Neurology.

“Aggregation is not the only endpoint,” noted senior author Robert Macdonald, M.D., Ph.D., the Margaret and John Warner Professor of Neurology and chairman of the department. “There’s also cell death … The protein is abnormal … (and) it forms these aggregates, which ultimately lead to cell dysfunction and death.”

If confirmed in humans, the findings suggest that drugs developed to treat neurodegenerative disorders such as ALS, Alzheimer’s or Parkinson’s disease could be “repurposed” to treat severe genetic epilepsies, the researchers concluded.

About 70 percent of epilepsies are genetic in nature, often resulting from mutations in ion channels such as the receptor for the neurotransmitter GABAA (gamma-aminobutyric acid).

Kang and Macdonald have been studying GABAA receptor mutations since 2003, when she joined his lab as a post-doctoral fellow. Kang earned her M.D. and Ph.D. degrees from Tongji Medical University in Wuhan, China, and studied neurodegeneration as a postdoc with Kenneth Maiese, M.D., at Wayne State University in Detroit.

After discovering an abnormal band of proteins in a biochemical test, the Vanderbilt researchers, who included Wangzhen Shen, M.D., and Chengwen Zhou, Ph.D., created a mouse model with a mutated GABAA receptor. The mutation caused behavioral abnormalities and seizures. It also was associated with aggregation of abnormal proteins.

The end of a subunit of the GABAA receptor is “truncated,” or snipped off, causing the protein to fold abnormally, Macdonald explained.

The abnormal proteins don’t insert into their proper position in the receptor in the cell membrane. Instead, they accumulate in the cell. That is what ultimately causes cell dysfunction and cell death.

The progressive brain disease associated with severe epileptic encephalopathy has been attributed to recurrent seizures. “We’re challenging that a little bit by saying that it’s not necessarily just the seizures themselves that cause the decline, but in fact the aggregated protein we think contributes to it,” Macdonald said.

“It opens a new chapter,” Kang added. The next step is to explore potential therapeutic approaches to alleviating protein aggregation, seizures and neurodegeneration in the mouse model, she said.

Dravet syndrome is a rare genetic disorder that occurs in roughly one in every 30,000 births, according to the Dravet Syndrome Foundation. Seizures are difficult to control and may be reduced by anticonvulsant drugs, although current treatment options are extremely limited.

The Vanderbilt study was supported by CURE (Citizen United for Research in Epilepsy), Dravet Syndrome Foundation,, and National Institutes of Health grants NS082635, NS051590, GM100701 and HD015052.

Recent Stories from VUMC News and Communications Publications

Vanderbilt Medicine
VUMC Voice