Breakthroughs in epilepsy and fragile X ataxia research
issue 19 | Fall 2013
In recent months, U-M neurologists and their research partners have reported two significant advances related to neurological diseases, based on laboratory findings they are now working to translate to clinical use. The work builds on U-M expertise in stem cells, advanced genetic techniques and managing complex neurogenetic conditions.
"EPILEPSY IN A DISH"
A new stem cell-based approach to studying epilepsy has yielded a surprising discovery about what causes a severe pediatric form of the disease and may help in the search for better medicines to treat all kinds of seizure disorders.
The findings were made using a technique that could be called "epilepsy in a dish." By turning skin cells of epilepsy patients into induced pluripotent stem cells, and then turning those stem cells into neurons, the team created a miniature testing ground for epilepsy research. In neurons derived from the cells of children who have the infantile-onset form of epilepsy called Dravet syndrome, measurements showed abnormally high levels of sodium current activity — including spontaneous bursts of communication and "hyperexcitability" that could potentially set off seizures. Control neurons made showed none of this abnormal activity. The work is published in Annals of Neurology. Further work in progress will create stem cell lines for other genetic forms of epilepsy.
Because the cells came from patients, they contained the hallmark seen in most patients with Dravet syndrome: a new mutation in SCN1A, the gene that encodes the crucial sodium channel protein called Nav1.1. That mutation reduces the number of channels to half the normal number in patients' brains.
Jack M. Parent, M.D., turned epilepsy patients' skin cells into stem cells and then neurons so he could study what made them seizure-prone.
"With this technique, we can study cells that closely resemble the patient's own brain cells without doing a brain biopsy," says senior author Jack M. Parent, M.D., professor of Neurology. "It appears that the cells are overcompensating for the loss of channels due to the mutation. These patient-specific induced neurons hold great promise for modeling seizure disorders and potentially screening medications."
ROOTS OF FRAGILE X ATAXIA FOUND
A bizarre twist on the usual way proteins are made may explain ataxia symptoms in the grandparents of some children with mental disabilities, according to U-M research recently published in the journal Neuron.
The condition, called fragile X-associated tremor ataxia syndrome (FXTAS), causes Parkinson's-like symptoms, and was first described only a decade ago. It most commonly affects adults who have grandchildren with fragile X syndrome, a genetic cause of intellectual disability and autism-like symptoms.
The common element in both conditions is a repeated DNA sequence in the FMR1 gene. Now, a U-M research team has discovered that a toxic protein they've named FMRpolyG contributes to the death of nerve cells in FXTAS — and that this protein is made in a very unusual way. The FXTAS mutation is a repeated DNA sequence that is made into RNA but normally is not made into protein because it lacks a start codon. However, the investigators discovered that when this repeat expands, it can trigger protein production by a new mechanism known as RAN translation.
Peter Todd, M.D., Ph.D., found a faulty sequence of DNA is made into protein, causing toxicity in the nerve cells.
Says neurologist and researcher Peter Todd, M.D., Ph.D., "Essentially, we've found that a sequence of DNA which shouldn't be made into protein is being made into protein — and that this causes a toxicity in nerve cells," he explains. "We believe that the protein forms aggregates, and that this is a contributor to toxicity and symptoms in FXTAS."
The team also demonstrated that blocking RAN translation prevents the repeat mutation from producing toxic results, suggesting a new target for future treatments. Their discovery could also have significance for other diseases such as amyotrophic lateral sclerosis and certain forms of dementia that are caused by DNA repeats.