Researchers, led by first author Ya-Fei Xu and senior authors Jada Lewis and Leonard Petrucelli, engineered mice that carry the wild-type human TDP-43 gene with the PrP promoter, so the protein is expressed in the brain and spinal cord. Homozygotes made approximately 2.5 times the TDP-43 normally found in mice. The human version actually edged out the mouse gene expression; transgenic animals had less mouse TDP-43 than non-transgenic mice, although they had more total TDP-43 protein.

Like previously reported mice that carry mutant human TDP-43 (TDP-43-A315T) driven by the PrP promoter (see ARF related news story on Wegorzewska et al., 2009), the Mayo Clinic animals exhibited low body and brain weights, as well as an impaired, “swimming” gait. These two PrP-based models, as well as mice with wild-type human TDP-43 with the mouse Thy-1 neuronal promoter (Wils et al., 2010), share insoluble TDP-43 aggregates and carboxyl-terminal truncation of the protein, both of which have been linked to disease pathology. As with the other models, the Mayo team found that TDP-43 was mostly nuclear, with occasional cytoplasmic redistribution that is not as severe as in human amyotrophic lateral sclerosis.

In addition, the Mayo scientists noticed large eosinophilic aggregates in the cytoplasm of spinal motor neurons in their model animals. When they examined these formations with electron microscopy, they discovered the aggregates were made of abnormal mitochondria. These mitochondrial clusters had fewer inner membrane folds, or cristae, than normal and vacuoles within the matrix, suggesting they were degenerating.

Mitochondria are always splitting up, via fission, and joining together, via fusion. If these processes were altered, it might cause abnormal aggregations. Accordingly, the scientists examined the fission-fusion machinery in the TDP-43 mice. The fission system, represented by Fis1 and phosphorylated DLP1, was upregulated in the model animals. Conversely, fusion protein mitofusin 1 levels dropped in animals with high levels of human TDP-43. Abnormal mitochondrial formations have been linked to ALS before, the authors note (Sasaki and Iwata, 1999; Mori et al., 2008; Sotelo-Silveira et al., 2009). They suggest that problems with TDP-43’s normal nuclear activity lead—indirectly, perhaps by altering gene expression—to disrupted mitochondrial trafficking or misregulated fission and fusion. This could then cause the mitochondrial aggregation.—Amber Dance.

Reference:
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):15851-9. Abstract