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Pesiridis GS, Tripathy K, Tanik S, Trojanowski JQ, Lee VM. A "two-hit" hypothesis for inclusion formation by carboxyl-terminal fragments of TDP-43 protein linked to RNA depletion and impaired microtubule-dependent transport. J Biol Chem. 2011 May 27;286(21):18845-55. PubMed.
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Boston University School of Medicine
The "two-hit" hypothesis is consistent with the involvement of TDP-43 in stress granule biology. RNA binding proteins, such as TDP-43, have an inherent tendency to form cytoplasmic aggregates upon exposure to a stress. This work is discussed in a number of manuscripts, including our manuscript (Liu-Yescevitz, 2010), Columbrita (2010), Dewey (2011), and MacDonald (2011).
The observation by Furukawa et al. is particularly interesting because it adds to a growing body of evidence that protein aggregates can be internalized and seed further aggregation. This has also been shown for Aβ and α-synuclein.
References:
Liu-Yesucevitz L, Bilgutay A, Zhang YJ, Vanderweyde T, Vanderwyde T, Citro A, Mehta T, Zaarur N, McKee A, Bowser R, Sherman M, Petrucelli L, Wolozin B. Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One. 2010;5(10):e13250. PubMed.
McDonald KK, Aulas A, Destroismaisons L, Pickles S, Beleac E, Camu W, Rouleau GA, Vande Velde C. TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum Mol Genet. 2011 Apr 1;20(7):1400-10. PubMed.
Dewey CM, Cenik B, Sephton CF, Dries DR, Mayer P, Good SK, Johnson BA, Herz J, Yu G. TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol Cell Biol. 2011 Mar;31(5):1098-108. PubMed.
Colombrita C, Zennaro E, Fallini C, Weber M, Sommacal A, Buratti E, Silani V, Ratti A. TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem. 2009 Nov;111(4):1051-61. Epub 2009 Sep 16 PubMed.
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