There is a new TDP-43 mouse in town. Having made its debut in Honolulu last month (see ARF related news story), the wild-type TDP-43-expressing animal from the Mayo Clinic in Jacksonville, Florida, is now in print in the August 11 Journal of Neuroscience.
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
- 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. PubMed.
- 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. PubMed.
- Sasaki S, Iwata M. Ultrastructural change of synapses of Betz cells in patients with amyotrophic lateral sclerosis. Neurosci Lett. 1999 Jun 11;268(1):29-32. PubMed.
- Mori F, Tanji K, Zhang HX, Nishihira Y, Tan CF, Takahashi H, Wakabayashi K. Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol. 2008 Aug;116(2):193-203. PubMed.
- Sotelo-Silveira JR, Lepanto P, Elizondo V, Horjales S, Palacios F, Martinez-Palma L, Marin M, Beckman JS, Barbeito L. Axonal mitochondrial clusters containing mutant SOD1 in transgenic models of ALS. Antioxid Redox Signal. 2009 Jul;11(7):1535-45. PubMed.
- Stallings NR, Puttaparthi K, Luther CM, Burns DK, Elliott JL. Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis. 2010 Nov;40(2):404-14. PubMed.
- Ritson GP, Custer SK, Freibaum BD, Guinto JB, Geffel D, Moore J, Tang W, Winton MJ, Neumann M, Trojanowski JQ, Lee VM, Forman MS, Taylor JP. TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J Neurosci. 2010 Jun 2;30(22):7729-39. PubMed.
- Kawamata H, Manfredi G. Mitochondrial dysfunction and intracellular calcium dysregulation in ALS. Mech Ageing Dev. 2010 Jul-Aug;131(7-8):517-26. PubMed.
- Tsai KJ, Yang CH, Fang YH, Cho KH, Chien WL, Wang WT, Wu TW, Lin CP, Fu WM, Shen CK. Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J Exp Med. 2010 Aug 2;207(8):1661-73. PubMed.
- Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ, Barber PC, Butler AC. Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann Neurol. 1998 Mar;43(3):380-3. PubMed.
- Martin LJ. Mitochondrial pathobiology in Parkinson's disease and amyotrophic lateral sclerosis. J Alzheimers Dis. 2010;20 Suppl 2:S335-56. PubMed.
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- 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. PubMed.