Ke YD, van Hummel A, Stevens CH, Gladbach A, Ippati S, Bi M, Lee WS, Krüger S, van der Hoven J, Volkerling A, Bongers A, Halliday G, Haass NK, Kiernan M, Delerue F, Ittner LM. Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS. Acta Neuropathol. 2015 Nov;130(5):661-78. Epub 2015 Oct 5 PubMed.

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  1. The paper by Walker and colleagues on the development and characterization of a novel TDP-43 mouse model is interesting and thorough. This research adds nicely to the increasing literature on inducible TDP-43 animal models, most notably in mice and rats, and highlights the importance of studying the consequences of post-developmental expression of TDP-43 forms. In this case, they demonstrate that widespread neuronal expression of a cytoplasmic form of TDP-43 (ΔNLS, for short) leads to several features of ALS/FTLD, including accumulation of insoluble cytoplasmic TDP-43, loss of endogenous nuclear TDP-43, motor neuron loss, muscle denervation, and progressive motor impairments. Remarkably, they show that transgene suppression decreases pathology, stops neuronal loss, improves motor deficits, and reduces mortality.

    As noted by Walker et al., we recently demonstrated the effects of short-term suppression of TDP-43- ΔNLS, but using a different promoter (CamKII) that drives expression predominantly in forebrain neurons, thus sparing lower motor neurons from transgene expression and subsequent degeneration (Alfieri et al., 2014). In these CamKII-ΔNLS inducible mice (Igaz et al., 2011), short-term transgene suppression at a young age led to recovery of behavioral deficits, including different domains affected in TDP-43 proteinopathies. Interestingly, the motor and cognitive phenotypes were recovered upon suppression, but not the social deficits, implicating differential vulnerability of underlying neuronal networks. In the NEFH-ΔNLS mice described here, non-motor phenotypes might be challenging to assess due to lower motor neuron degeneration and confounds emerging from profound motor deficits. In this light, both animal models represent complementary tools to address questions regarding the role of altered TDP-43 in ALS-like or FTLD-like phenotypes.

    It is interesting to note the convergence of some behavioral results from animal models with different initial mechanistic hypothesis. A recent mouse model, based on viral expression of C9ORF72 repeat expansions (Chew et al., 2015), develops TDP-43 cytoplasmic pathology and cortical neuron loss, and displays almost identical behavioral phenotypes to our CamKII-ΔNLS animals. In particular, decreased motor performance in the rotarod, hyperlocomotion, and increased anxiety-like behavior in the open-field test and impaired social interaction scores indicating social deficits. That these are all shared features of animals developed through quite different approaches reinforces the need for complementary animal models that will inform us, as a community, of the commonalities and specifics of etiological mechanisms. These novel NEFH-ΔNLS mice presented here also contribute to this idea.

    The results from this study from Virginia Lee’s lab also emphasize the complexity of an unresolved question in the field, i.e. the role of pathology (in the form of aggregates or inclusions) in cell function and survival.

    References:

    Alfieri JA, Pino NS, Igaz LM. Reversible behavioral phenotypes in a conditional mouse model of TDP-43 proteinopathies. J Neurosci. 2014 Nov 12;34(46):15244-59. PubMed.

    Chew J, Gendron TF, Prudencio M, Sasaguri H, Zhang YJ, Castanedes-Casey M, Lee CW, Jansen-West K, Kurti A, Murray ME, Bieniek KF, Bauer PO, Whitelaw EC, Rousseau L, Stankowski JN, Stetler C, Daughrity LM, Perkerson EA, Desaro P, Johnston A, Overstreet K, Edbauer D, Rademakers R, Boylan KB, Dickson DW, Fryer JD, Petrucelli L. Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science. 2015 Jun 5;348(6239):1151-4. Epub 2015 May 14 PubMed.

    Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, Unger T, Malunda J, Xu Y, Winton MJ, Trojanowski JQ, Lee VM. Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest. 2011 Feb;121(2):726-38. Epub 2011 Jan 4 PubMed.

    View all comments by Lionel Muller Igaz

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