Alexander’s disease is a disease linked to mutations in the GFAP gene. The mechanisms that cause these mutations to cause disease are not yet understood. In addition, the age of onset, the severity of symptoms and the rate of progression vary widely between patients, and the data available to us are too limited to explain this heterogeneity. In recent years, we have published the results of two studies that attempt to answer these questions using mouse models of the disease and brain samples taken during autopsies from patients with Alexander disease.

In the first study, published last year in the Journal of Neuroscience, we identified a potential link between the mechanisms responsible for neurodegeneration in Alexander disease and other more common neurodegenerative diseases. These results relate to a specific protein called TDP-43, which regulates the expression of other genes. This protein was already known in amyotrophic lateral sclerosis (ALS) and about 50% of cases of frontotemporal lobar degeneration (DLFT), a type of dementia in these cases referred to as DLFT-TDP. In ALS and DLFT-TDP, the TDP-43 protein becomes insoluble, is biochemically altered, and improperly localised in neurons and glia of the brain and spinal cord.

The TDP-43 protein had previously been detected in the Rosenthal fibers of certain brain tumors. We therefore tested for its presence in Rosenthal fibers characteristic of Alexander disease. We have found that the TDP-43 protein is indeed altered and incorrectly localised in the brains of patients with Alexander disease as well as in mouse models of the disease, which also contain Rosenthal fibers. TDP-43 is now the focus of attention of researchers working with Alexander disease.

In the second study, published late last year in Brain Research, we examined the possible role of environmental factors, such as head trauma, in modifying the severity of symptoms in patients with Alexander disease. Often, families and patients report rapid onset of new symptoms or rapid progression of pre-existing symptoms after seemingly minor head injuries. Head trauma is a known risk factor for epilepsy. Using our mouse models, we first performed electroencephalograms and found that even without injury, mice show signs of subconvulsive epilepsy.

We then subjected these mice to slightly traumatic head injuries, but enough to increase the risk of epilepsy. However, we were unable to show that GFAP mutant mice differed from control mice in terms of risk of epilepsy following trauma.

Upcoming research topics include the development of new animal models and the development or identification of drugs that could alter the course of the disease.