<figcaption>A motor neuron from an ALS patient showing cytoplasmic inclusions composed of TDP-43 and ubiquitin (yellow fluorescence). Credit: Courtesy of Manuela Neumann</figcaption>
A motor neuron from an ALS patient showing cytoplasmic inclusions composed of TDP-43 and ubiquitin (yellow fluorescence). Credit: Courtesy of Manuela Neumann

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.1 Discovered in 1995, TDP-43 had only been studied in the context of cystic fibrosis and HIV, not neurodegenerative diseases.

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.3 "I think there is just cause now that the appropriate target for biomarker and drug target studies to go after for ALS is TDP-43, not SOD1," Trojanowski says.

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.4 Interestingly, all of the TDP-43 mutations identified thus far are dominant, and FTLD-U and some ALS patients are heterozygous for mutant TARDBP. This suggests that the mutant protein causes neurodegeneration through a toxic gain of function rather than a loss of normal protein function that would require the homozygous recessive condition, according to Gitler.

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.5 Gitler and colleagues demonstrated that over expression of TDP-43 results in relocalization of the protein from the nucleus to the cytoplasm - as occurs in ALS and FTLD - and toxicity. He is now investigating the effects of the documented TDP-43 mutations on yeast cells and studying zebra fish models with mutant TDP-43 genes.

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.6 Data like these may be just the beginning of TDP-43's impact on science's understanding of neurodegeneration. "This discovery, in the next five or ten years, may turn out to be even more important," says Lee.

Data derived from the Science Watch/Hot Papers database and the Web of Science (Thomson ISI) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. M. Neumann et al., "Ubiquinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis," Science, 314:130-3, 2006. (Cited in 198 papers)


1. M. Neumann et al., "Ubiquinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis," Science, 314:130-3, 2006. (Cited in 198 papers) 2. L. Kwong et al., "TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease," Acta Neuropathol, 114:63-70, 2007. 3. I. Mackenzie et al, "Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations," Ann Neurol, 61:427-34, 2007. 4. J. Sreedharan et al., "TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis," Science, 319:1668-72, 2008. 5. B. Johnson et al., "A yeast TDP-43 proteinopathy model: Exploring the molecular determinant of TDP-43 aggregation and cellular toxicity," Proc Natl Acad Sci, 105:6439-44, 2008. 6. P. Foulds et al., "TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer's disease and frontotemporal lobar degeneration," Acta Neuropathol, 116:141-6, 2008.

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