Amyotrophic Lateral Sclerosis (ALS) is a deadly neurodegenerative disease characterized by a precipitous loss of motor neuron function. From the time researchers first named the disease, the key protein that either causes ALS or accumulates because of the disease remained a mystery.
Then, in 2006, a research team led by University of Pennsylvania neuroscientists found TAR DNA-binding protein 43 (TDP-43) lurking in the protinaceous inclusions that spider through the neurons of many ALS patients, as described in this month's Hot Paper.
The research team initially was searching for the protein causing frontotemporal lobar degeneration with ubiquinated inclusions (FTLD-U) - a dementia-causing disorder related to ALS. The team screened...
A discovery resisted
"When we identified TDP-43 as the disease protein, there were still a lot of naysayers saying that this might not be relevant for ALS," recalls Lee. In 1993 researchers found mutations in the superoxide dismutase 1 (SOD1) gene which were thought to account for most cases of inherited ALS. Inherited ALS only accounts for about 5% of ALS cases, though; the majority are sporadic. "The assumption was that SOD1 explained not only familial ALS, but all sporadic ALS cases," says UPenn neuroscientist and senior author of the Hot Paper John Trojanowski. "We had to go up against the SOD1-ers." In 2007, Trojanowski's group found pathological TDP-43 in more cases of sporadic ALS and in cases of familial ALS where SOD1 mutations did not play a role.
But much about TDP-43's exact role in ALS remains to be fully understood. The function of the protein, which is normally located in the nuclei of neurons, is to stabilize mRNA and influence exon splicing or transcription. Whether it's the loss of this normal function or the toxic effects of malfunctioning TDP-43 that leads to neurodegenerative diseases has not been adequately explained.
In 2008, researchers found about 15 different mutations in TARDBP, the gene for TDP-43, for abnormal protein accretion in the nervous tissue of FTLD-U, and familial and sporadic ALS patients.
Jeffery Rothstein, a neurologist at Johns Hopkins, says that TDP-43-based diagnostic tools or treatments may become a reality, but more research will be required to fully understand the protein's specific physiological role in neurodegeneration. "We have an important new clue," he says. "I have no way of knowing whether it will be valuable or not." But that shouldn't hinder progress, says Trojanowski. "We don't have to wait for that to launch drug discovery efforts."
The race for a model
The field anxiously awaits a murine model of ALS using mutations, knockouts, and over expression of TDP-43. According to Lucie Bruijn, senior vice president for research and development at The ALS Association, several labs are currently working on mouse and fly models using TDP-43, but none are ready for prime time quite yet. "I'm hoping the model will be made in a year or two with some luck," Trojanowski says.
In the meantime Gitler has already created a yeast model of TDP-43-mediated proteinopathies.
Already, measuring TDP-43 levels in plasma is showing promise as a biomarker in some patients with probable frontotemporal lobar degeneration or with Alzheimer's disease. This May, a team from the United Kingdom found elevated TDP-43 levels in the brain of about 46% of the FTLD patients and about 22% of the Alzheimer's patients they tested.