Alexander disease is a rare neurological disorder that carries a grim prognosis. It involves a dangerous accumulation of the glial fibrillary acidic protein, GFAP, in the brain that causes destruction of white matter, leading to serious cognitive and motor function deficits. There is limited research surrounding this fatal disease and no known cure.
Previous research explained the trademark protein accumulation by assuming an Alexander disease patient had a reduced ability to degrade and clear the protein. However, a recent study discovered the rate of GFAP protein degradation is actually increased in the pathology of the disease.
An important concept to consider when discussing Alexander disease is turnover. Turnover is a combination of the synthesis and the degradation of a protein, explained Albee Messing, director of the UW-Madison Waisman Center and principal investigator of the study.
Proteins are synthesized, then degraded. Turnover can be conceptualized as generations of people, they are born and then they die at some age. After this, the next generation of people takeover. The turnover rate is essentially the amount of time between generations of protein. High or low turnover means the generations occur faster or slower, respectively.
“There were lots of signs that degradation was impaired, and that’s why we were really surprised that it increased,” said Messing.
In Alexander disease, the mutant GFAP protein is known to be overproduced. The novel idea here is that the protein degradation actually increases as well. But, there is a lag between the overproduction and the eventual compensation by the increase in degradation. This lag explains the sustained increase in, and ultimately the accumulation of, the GFAP protein in the brain.
Messing says that the main goal of the lab now is to find a way to treat Alexander disease by focusing on stopping the synthesis of the GFAP protein.
“We’re trying to treat the disease it,” said Messing, definitively, as he described the therapeutic techniques the lab will focus on in the future.
Gene editing has been highly sensationalized in the media recently, and therapeutic human genome editing is still hotly debated. However, Alexander disease researchers manage to stay out of the crossfire.
In the case of Alexander disease, as well as many diseases of the brain, neuropathies, gene editing is impractical with current techniques. In order for gene editing to be useful, the cells need to regrow rapidly. Since brain cells are not fast to regenerate, the therapeutic value for human gene editing in Alexander disease is minimal .
“CRISPR [gene editing] is certainly something that is a possibility in a dish, and we’re actually doing that in cultures right now … but cells in the brain don’t repopulate quickly,” said Messing.
The lab’s main focus right now is on drugs that directly target the overproduction of the GFAP protein. The research will continue without Laura Moody, the first author on this research paper and former student in Messing’s lab.
“Laura was a grad student here on campus, and then became a post-doc in my lab … she worked on [this project] for maybe five or six years, it takes a lot of patience,” said Messing.
The paradigm shift that was detailed in this recent publication highlights the need reason to invest time as well as and resources in Alexander disease research. There is still much we don’t know about this devastating illness. But with discoveries like the one made by Messing and Moody, families suffering from the disease are could be much closer to a treatment than they were before.