Reduction of tau protein improves symptoms in model of severe childhood epilepsy

August 13, 2014, Gladstone Institutes
Generalized 3 Hz spike and wave discharges in a child with childhood absence epilepsy. Credit: Wikipedia.

Researchers at the Gladstone Institutes have shown that reducing brain levels of the protein tau effectively blocks the development of disease in a mouse model of Dravet syndrome, a severe intractable form of childhood epilepsy. This therapeutic strategy not only suppressed seizure activity and premature death, but also improved cognitive and behavioral abnormalities that can accompany this syndrome.

Previous studies from this group have shown that lowering tau levels reduces abnormal brain activity in models of Alzheimer's disease, but this is the first demonstration that tau reduction may also be beneficial in intractable genetic epilepsy.

"It would really be wonderful if tau reduction turned out to be useful not only in Alzheimer's disease, but also in other disabling neurological conditions for which there currently are no effective treatments," said senior author Lennart Mucke, MD, the director of the Gladstone Institute of Neurological Disease and a professor of Neurology and Neuroscience at the University of California, San Francisco. "We suspected that this approach might be beneficial in Dravet, but we couldn't be sure because of the severity of this syndrome and the corresponding model. We are thrilled that our strategy was so effective, but a lot more work is needed to advance it into the clinic."

Dravet syndrome is one of the most challenging forms of , resulting from a specific genetic mutation that affects sodium channels in the brain. Frequent, relentless seizures are accompanied by cognitive impairments and behavioral problems similar to autism, and up to 20% of patients succumb to sudden death. Current treatments for Dravet syndrome are largely ineffective, making research into the disorder particularly urgent.

"I am especially excited about the improvements we observed in cognitive and behavioral dysfunctions because these abnormalities are particularly hard on the kids—and their parents," said first author Ania Gheyara, MD, PhD, a staff scientist at Gladstone who is also affiliated with the UCSF Department of Pathology. "Our hope is that this approach will be broadly applicable to many different types of epilepsy."

In the study, which was published online today in the Annals of Neurology, the scientists reduced the level of the by genetically engineering Dravet mouse models, "knocking out" the gene associated with tau production. The deletion of one copy of the gene resulted in substantial improvements in most symptoms, while deleting both copies eliminated them almost completely. This included a significant reduction in both spontaneous and heat-induced seizures. The latter were used to mimic the fever-related seizures that are often seen in the early stages of Dravet syndrome. Network activity in the brain was also normalized, providing additional support for the remarkable ability of tau reduction to suppress epileptic activity.

Additionally, tau reduction ameliorated the learning and memory deficits and present in the Dravet mice, which may relate to the cognitive impairments and autism-like behaviors seen in the human condition.

"The next steps are to develop tau-lowering therapeutics that could be used in humans and to evaluate their safety and efficacy in preclinical studies," said Dr. Mucke, "objectives we are pursuing actively."

Explore further: Less tau reduces seizures and sudden death in severe epilepsy

Related Stories

Less tau reduces seizures and sudden death in severe epilepsy

January 22, 2013
Deleting or reducing expression of a gene that carries the code for tau, a protein associated with Alzheimer's disease, can prevent seizures in a severe type of epilepsy linked to sudden death, said researchers at Baylor ...

Competing impairment of neurons governs pathology of a severe form of epilepsy

September 20, 2013
Dravet syndrome is a rare and severe form of epilepsy caused primarily by inherited loss-of-function mutations in a gene called SCN1A. This gene encodes a sodium ion channel known as Nav1.1 and is required for the proper ...

European epilepsy consortium identifies new gene for severe childhood epilepsy

January 22, 2014
A European consortium of epilepsy researchers has reported the discovery of a new gene involved in severe childhood epilepsy. Using a novel combination of technologies, including trio exome sequencing of patient/parental ...

Brain cell activity regulates Alzheimer's protein

February 26, 2014
Increased brain cell activity boosts brain fluid levels of a protein linked to Alzheimer's disease, according to new research from scientists at Washington University School of Medicine in St. Louis.

Team discovers a way to potentially slow down Alzheimer's disease

March 20, 2014
Researchers at the University of Texas Medical Branch at Galveston have discovered a way to potentially halt the progression of dementia caused by accumulation of a protein known as tau.

Could cannabis curb seizures? Experts weed through the evidence

May 22, 2014
The therapeutic potential of medical marijuana and pure cannabidiol (CBD), an active substance in the cannabis plant, for neurologic conditions is highly debated. A series of articles published in Epilepsia, a journal of ...

Recommended for you

Your brain responses to music reveal if you're a musician or not

January 23, 2018
How your brain responds to music listening can reveal whether you have received musical training, according to new Nordic research conducted in Finland (University of Jyväskylä and AMI Center) and Denmark (Aarhus University).

New neuron-like cells allow investigation into synthesis of vital cellular components

January 22, 2018
Neuron-like cells created from a readily available cell line have allowed researchers to investigate how the human brain makes a metabolic building block essential for the survival of all living organisms. A team led by researchers ...

Finding unravels nature of cognitive inflexibility in fragile X syndrome

January 22, 2018
Mice with the genetic defect that causes fragile X syndrome (FXS) learn and remember normally, but show an inability to learn new information that contradicts what they initially learned, shows a new study by a team of neuroscientists. ...

Epilepsy linked to brain volume and thickness differences

January 22, 2018
Epilepsy is associated with thickness and volume differences in the grey matter of several brain regions, according to new research led by UCL and the Keck School of Medicine of USC.

Research reveals atomic-level changes in ALS-linked protein

January 18, 2018
For the first time, researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases ...

Fragile X finding shows normal neurons that interact poorly

January 18, 2018
Neurons in mice afflicted with the genetic defect that causes Fragile X syndrome (FXS) appear similar to those in healthy mice, but these neurons fail to interact normally, resulting in the long-known cognitive impairments, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.