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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.
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Comments
University of Antwerp
This study elegantly gives a first insight on a transgenic mouse model of mutant TDP-43 (A315T) identified in familial ALS patients. For those in the field, it is clear that generating these mouse models is a mammoth task on its own. Among the many interesting findings in this paper, the first to catch my attention was that the 25-kDa TDP-43 C-terminal fragments (CTFs) were recovered from detergent-soluble fractions but not from urea fractions as observed in sporadic and familial ALS/FTLD patients. If the TDP-43 25-kDa CTFs would indeed be confirmed as the real culprit, this would yet again emphasize the importance of soluble but not aggregated protein/peptide in cellular toxicity, as has been shown for a number of other proteinopathies including Aβ, α-synuclein, polyglutamine expansion in Huntingtin, and mutant SOD1.
Another important observation made in this paper was that ubiquitin-immunoreactive (ir) inclusions observed in select neurons including motor neurons were not TDP-43-ir. Thus, the mutant TDP-43 (A315T) mice do not completely model ALS, where ubiquitin-ir inclusions are also TDP-43-ir; nevertheless, this work does lead to a very interesting question: what are these inclusions composed of?
Knowing earlier studies (see Tatom et al., 2009 and ARF related news story), I am also not surprised at the glaring omission of wild-type TDP-43 mice as a better control than the non-transgenic mice utilized in this study. So although clearly not all is answered yet, let's see how these and other TDP-43 mouse models currently being developed will unfold the mysteries of TDP-43-led neurodegeneration.
References:
Tatom JB, Wang DB, Dayton RD, Skalli O, Hutton ML, Dickson DW, Klein RL. Mimicking aspects of frontotemporal lobar degeneration and Lou Gehrig's disease in rats via TDP-43 overexpression. Mol Ther. 2009 Apr;17(4):607-13. PubMed.
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