19 Mar 2010

TDP-43 clogs neurons in some cases of amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer disease. But what does this rogue protein actually do? Researchers are tackling the problem with mice lacking its gene. According to a paper posted online by Acta Neuropathologica on March 3, TDP-43 is essential in embryogenesis, and even a slight deficit in the protein causes motor deficits in older animals. Brian Kraemer of the University of Washington in Seattle led the work with colleagues there and at the University of Pennsylvania in Philadelphia.

TDP-43 has been linked to RNA processing and trafficking, but its exact job is unclear (Freibaum et al., 2010). The protein normally hangs out in the nucleus, but often piles up in the cytoplasm in disease models (see ARF related news story on Barmada et al., 2010). Researchers theorize that TDP-43 mutations, found in some instances of human disease, can cause both a loss of the protein’s normal nuclear function and a toxic gain of function in the cytoplasm (see ARF related news story on Zhang et al., 2009). The current work supports the possibility that loss of TDP-43 causes disease, but does not preclude a gain of function, Kraemer said.

A loss-of-function hypothesis makes sense, the study authors reasoned, if TDP-43 is normally needed in neurons. To test this idea, Kraemer and colleagues engineered mice carrying a knockout allele. Heterozygotes were healthy, but homozygotes died in utero, showing that TDP-43 is essential in development. When the researchers analyzed TDP-43 protein in heterozygous mice, they found nearly wild-type amounts, suggesting cells regulate TDP-43 expression to maintain normal levels.

The work mirrors that in two other recent papers. Researchers in Texas and Taiwan also found that the TDP-43 knockout is lethal, but heterozygotes are okay (Sephton et al., 2010; Wu et al., 2010). Those researchers found no defects in their young heterozygous animals. Kraemer followed his mice longer, testing them for motor defects at one year or older. “It is only as they age that you start to see motor defects,” he said. The heterozygotes had a weaker forelimb grip, and were unable to hang upside-down on a wire grid as long as wild-type control mice. “It is a little bit of an odd phenotype,” Kraemer said, because although the muscle deficiency arose with age, it was not progressive like neurodegenerative disease.

The researchers also looked for pathological evidence of neurodegeneration and muscle atrophy in the aging heterozygotes. “There is nothing obvious,” Kraemer said. “We are not sure what is wrong with these mice at the molecular level.” Given that the heterozygotes have near-normal TDP-43 protein levels, perhaps subtle non-structural abnormalities, in metabolism, for example, might account for the muscle weakness, the authors suggest.

The logical next step is a conditional knockout that could survive to adulthood before scientists take away its TDP-43. Several labs are in the early stages of such a project, wrote Virginia Lee of the University of Pennsylvania and a co-author on the paper, in an e-mail to ARF.—Amber Dance

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References

News Citations

1. TDP-43: Modified and On the Move 22 Jan 2010
2. Toxic TDP-43 Truncates Point to Gain-of-Function Role in Disease 24 Apr 2009

Paper Citations

1. Freibaum BD, Chitta RK, High AA, Taylor JP. Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res. 2010 Feb 5;9(2):1104-20. PubMed.
2. Barmada SJ, Skibinski G, Korb E, Rao EJ, Wu JY, Finkbeiner S. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci. 2010 Jan 13;30(2):639-49. PubMed.
3. Zhang YJ, Xu YF, Cook C, Gendron TF, Roettges P, Link CD, Lin WL, Tong J, Castanedes-Casey M, Ash P, Gass J, Rangachari V, Buratti E, Baralle F, Golde TE, Dickson DW, Petrucelli L. Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A. 2009 May 5;106(18):7607-12. PubMed.
4. Sephton CF, Good SK, Atkin S, Dewey CM, Mayer P, Herz J, Yu G. TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem. 2010 Feb 26;285(9):6826-34. PubMed.
5. Wu LS, Cheng WC, Hou SC, Yan YT, Jiang ST, Shen CK. TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis. 2010 Jan;48(1):56-62. PubMed.

Further Reading

Papers

1. Ticozzi N, LeClerc AL, van Blitterswijk M, Keagle P, McKenna-Yasek DM, Sapp PC, Silani V, Wills AM, Brown RH Jr, Landers JE. Mutational analysis of TARDBP in neurodegenerative diseases. Neurobiol Aging. 2011 Nov;32(11):2096-9. Epub 2009 Dec 23 PubMed.
2. Nishimoto Y, Ito D, Yagi T, Nihei Y, Tsunoda Y, Suzuki N. Characterization of alternative isoforms and inclusion body of the TAR DNA-binding protein-43. J Biol Chem. 2010 Jan 1;285(1):608-19. PubMed.
3. Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18809-14. Epub 2009 Oct 15 PubMed.
4. Pesiridis GS, Lee VM, Trojanowski JQ. Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis. Hum Mol Genet. 2009 Oct 15;18(R2):R156-62. PubMed.
5. Arai T, Hasegawa M, Nonoka T, Kametani F, Yamashita M, Hosokawa M, Niizato K, Tsuchiya K, Kobayashi Z, Ikeda K, Yoshida M, Onaya M, Fujishiro H, Akiyama H. Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy. Neuropathology. 2010 Apr;30(2):170-81. PubMed.
6. Nonaka T, Kametani F, Arai T, Akiyama H, Hasegawa M. Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43. Hum Mol Genet. 2009 Sep 15;18(18):3353-64. PubMed.

News

1. Going Wild About the Latest TDP-43 Mouse Models 4 Feb 2010
2. Research Brief: There’s a Fly in My TDP-43 Research 29 Jan 2010
3. Meet the First Published TDP-43 Mouse 16 Oct 2009
4. London, Ontario: TDP-43 Across the Animal Kingdom at ALS Meeting 6 Jul 2009
5. TDP-43 Roundup: New Models, New Genes 7 Mar 2009
6. Heady Times for Researchers Studying TDP-43 21 Apr 2008
7. Toxic TDP-43 Truncates Point to Gain-of-Function Role in Disease 24 Apr 2009
8. TDP-43: Modified and On the Move 22 Jan 2010