6 March 2009. TAR DNA binding protein-43 has risen from relative obscurity just a few years ago to become a superstar in studies of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. In 2006, scientists reported that TDP-43 inclusions are a hallmark of both diseases (Neumann et al., 2006). Last year, researchers discovered multiple TARDBP mutations in people with familial ALS (see ARF related news story, Gitcho et al., 2008, and Sreedharan et al., 2008), and since then, rapid-fire new data about the genetics and pathology of TDP-43 proteinopathy have kept the protein at the forefront of research.
Key to future TDP-43 studies will be rodent models that overexpress the protein. Scientists from the Louisiana State University Health Sciences Center in Shreveport reported the first such model in a paper published online February 17 in Molecular Therapy. First author Jason Tatom, principal investigator Ronald Klein, and colleagues injected an adeno-associated virus vector bearing the wild-type human TARDBP gene into the substantia nigra of rats. The animals then expressed approximately three times the normal amount of TDP-43 in the nigra and developed some characteristics of human TDP-43 disease. Primarily a nuclear protein, TDP-43 moved into the cytoplasm in approximately 1 percent of transduced cells. The excess TDP-43 was toxic to dopaminergic neurons.
“I thought it was a good first effort at modeling TDP-43 pathology in an animal,” said Brian Kraemer of the University of Washington in Seattle, who was not involved in the study. “The fact that they saw toxicity with wild-type TDP-43 is encouraging,” he said, because the majority of patients who exhibit TDP-43 inclusions do not have mutations in the gene.
“Having an AAV-based TDP-43 rodent model is not a substitution for a rodent model with stable germline transmission,” Samir Kumar-Singh of VIB—University of Antwerp, Belgium, also not involved in the study, wrote in an e-mail to ARF (see full comment below). “But until these models are developed, expression of TDP-43 by AAV-mediated somatic cell transfer approaches will continue to shed light on TDP-43-mediated disease mechanisms.”
At Washington University in St. Louis, Missouri, scientists are working on modeling a specific subset of TDP-43 diseases, that is, frontotemporal lobar degeneration due to a mutation in the valosin-containing protein (VCP) gene. Mutations in this gene are rare; principal investigator Nigel Cairns estimates they exist in approximately 20 American families. The mutations cause FTLD with inclusion body myopathy and Paget disease of bone. VCP has a number of cellular functions. It acts as a co-chaperone for the membrane fusion machinery, mediates endoplasmic reticulum-associated degradation of proteins, and plays a role in cell survival. Cairns, first author Michael Gitcho, and colleagues surveyed how VCP mutations affected various cellular processes. Their work appeared online February 23 in the Journal of Biological Chemistry. Expressing VCP mutants in neuroblastoma cells altered TDP-43 localization, sending it into the cytoplasm, as happens in human disease. The mutations also decreased proteasome activity, and ultimately killed cells.
On the human genetics front, the number of known TARDBP mutations continues to climb; last month, two Italian groups announced new ones in people with ALS. Writing February 17 in Human Mutation online, Lucia Corrado of the University of Eastern Piedmont in Novara, Italy, and colleagues reported nine new mutations. Two of those mutations were also discovered by Roberto Del Bo of the University of Milan and colleagues, whose own results were released online February 19 by the European Journal of Neurology.
TDP-43 offers researchers plenty to think about, and some suggest it is the central feature in a single disorder whose spectrum spans both FTLD and ALS (Geser et al., 2009 and see ARF related news story). Others are holding their applause as they wait for more evidence. “Are we at the point where we want to say that TDP-43 is the β amyloid of frontotemporal dementia?” asked Conrad Weihl, also of Washington University, who was not involved with the current research. “I’m worried that people are jumping to that conclusion,” although, he admitted, “It may well be correct.”—Amber Dance.
Tatom JB, Wang DB, Dayton RD, Skalli O, Hutton ML, Dickson DW, Klein RL. Mimicking aspects of frontotemporal lobal degeneration and Lou Gehrig’s disease in rats via TDP-43 expression. Mol Ther 2009 Feb 17 [Epub ahead of print]. Abstract
Gitcho MA, Strider J, Carter D, Taylor-Reinwald L, Forman MS, Goate AM, Cairns AM. VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death. J Biol Chem 2009 Feb 23 [Epub ahead of print]. Abstract
Corrado L, Ratti A, Gellera C, Buratti E, Castellotti B, Carlomagno Y, Ticozzi N, Mazzini L, Testa L, Taroni F, Baralle FE, Silani V, D’Alfonso S. High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis. Hum Mutat 2009 Feb 17 [Epub ahead of print]. Abstract
Del Bo R, Ghezzi S, Corti S, Pandolfo M, Ranieri M, Santoro D, Ghione I, Prelle A, Orsetti V, Mancuso M, Sorarù G, Briani C, Angelini C, Siciliano G, Bresolin N, Comi GP. TARDBP(TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations. Eur J Neurol 2009 Feb 19 [Epub ahead of print]. Abstract