This is a fascinating study on yet another TDP-43 transgenic mouse model driven by the mouse Thy1.2 promoter. The most notable outcome to catch my attention was that TDP-43 intranuclear inclusions in motor neurons did not colocalize with survival motor neuron (SMN)-associated Gemini of coiled bodies (GEMs), but with a non-snRNP marker SC35, as well as with fused in sarcoma (FUS). FUS is another recently identified nuclear protein associated with ALS, and functional complexes of TDP-43 and FUS are beginning to be identified at the endogenous protein levels (Kim et al., 2010). Whether transiently increased TDP-43 pathologically sequesters FUS in ALS/FTLD remains to be shown. Also, whether such TDP-43 needs to be ubiquitinated or phosphorylated to be pathological remains to be studied.

The emerging consensus shows that although such inclusions might only be infrequently or weakly ubiquitinated, these might contain some amounts of phosphorylated TDP-43 as detected by phospho-specific p409/410 TDP-43 antibodies (Wils et al., 2010). On the other hand, the present study clearly...  Read more

This is a fascinating study on yet another TDP-43 transgenic mouse model driven by the mouse Thy1.2 promoter. The most notable outcome to catch my attention was that TDP-43 intranuclear inclusions in motor neurons did not colocalize with survival motor neuron (SMN)-associated Gemini of coiled bodies (GEMs), but with a non-snRNP marker SC35, as well as with fused in sarcoma (FUS). FUS is another recently identified nuclear protein associated with ALS, and functional complexes of TDP-43 and FUS are beginning to be identified at the endogenous protein levels (Kim et al., 2010). Whether transiently increased TDP-43 pathologically sequesters FUS in ALS/FTLD remains to be shown. Also, whether such TDP-43 needs to be ubiquitinated or phosphorylated to be pathological remains to be studied.

The emerging consensus shows that although such inclusions might only be infrequently or weakly ubiquitinated, these might contain some amounts of phosphorylated TDP-43 as detected by phospho-specific p409/410 TDP-43 antibodies (Wils et al., 2010). On the other hand, the present study clearly shows that the number of GEM bodies was significantly increased in TDP-43-overexpressing mice while being absent in conditional TDP-43 knockout mice, and considering the importance of GEMs/SMN in RNA metabolism, this could be pathogenic in either direction. Despite a mild increase in cleaved caspases, an overt neuronal loss was not noticed here, although it is not clear at what disease stage this was looked at. A clear neuronal loss was observed in other wild-type and mutant TDP-43 mice at end-disease stages and might be secondary to axonal degeneration (Wegorzewska et al., 2009; Wils et al., 2010). And lastly, aggregation of mitochondria seems to be a common feature of many such TDP-43-overexpressing mice (Shan et al., 2010; Xu et al., 2010) including our own model (Wils et al., 2010); however, yet again, the clinical significance of these findings is being sought in ALS/FTLD patients and promises encouraging data.

References:
Kim SH, Shanware N, Bowler MJ, Tibbetts RS. ALS-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to coregulate HDAC6 mRNA. J Biol Chem. 2010 Aug 18. Abstract

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. Abstract

Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, Smits V, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3858-63. Abstract

Xu YF, Gendron TF, Zhang YJ, Lin WL, D'Alton S, Sheng H, Casey MC, Tong J, Knight J, Yu X, Rademakers R, Boylan K, Hutton M, McGowan E, Dickson DW, Lewis J, Petrucelli L. Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci. 2010 Aug 11;30(32):10851-9. Abstract

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