Mutations: TARDBP A315T
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J
Genetic Background: C57BL/6J x CBA mice backcrossed to C57BL/6J.
Availability: The Jackson Lab: Stock# 010700; Live
This page describes a congenic version of the TARDBP (A315T) model originally generated by Robert Baloh and colleagues on a mixed C57Bl/6/J and CBA background (Wegorzewska et al., 2009). Characterization of the congenic animal is complicated by a severe gastrointestinal phenotype, which leads to ill-health and premature death (Hatzipetros et al., 2013; Guo et al., 2012). Consuming an easily digestible gel diet can stave off GI dysfunction and allow time for pathology to develop in the brain and spinal cord, although spinal motor neuron loss remains largely absent despite distal axon degeneration (Herdewyn et al., 2014).
Congenic TARDBP (A315T) mice appear relatively healthy until about three months of age, when they begin to lose weight and show signs of declining health, such as decreased grooming. At this time, mice exhibit signs of gastrointestinal dysfunction, such as a swollen and tender abdomen. The age at which symptoms first appear varies, but after onset, the mice decline rapidly and die within days to weeks (Hatzipetros et al., 2013; Guo et al., 2012).
In general, males have an earlier onset and more rapid progression than females, although lifespan varies. One study found median lifespan on a standard diet to be 84 days for males and 126 days for females (Herdewyn et al., 2014). Another study found the median lifespan to be 108 days for males and 185 days for females (Hatzipetros et al., 2013). On a normal diet, the lifespan of both sexes is limited by GI dysfunction and can be extended by replacing standard chow with an easily digestible gel. This diet allows the mice to reach more advanced ages and to develop progressive motor deficits and motor neuron degeneration (Herdewyn et al., 2014). In mice fed a gel diet, significant axonal degeneration was observed, resulting in about 20 percent reduced innervation of neuromuscular junctions (Herdewyn et al., 2014). Compelling motor neuron degeneration was not observed in mice consuming a standard diet (e.g., Hatzipetros et al., 2013; Esmaeili et al., 2013), possibly because fatal GI dysfunction cut short disease progression.
Bona fide neuronal loss appears to be rare in this model regardless of diet. Cortical neuron loss has not been examined in detail in this exact model, but when crossed with a Thy-1YFP model to label layer 5 pyramidal neurons, the mice had fewer of these neurons at 15 weeks of age than YFP littermate controls (Zhang et al., 2016). Neuronal numbers in the spinal cord appear to be largely stable in mice consuming standard chow or a gel diet (e.g., Esmaeili et al., 2013; Hatzipetros et al., 2013; Herdewyn et al., 2014); however, one study found 20 percent loss of lower motor neurons at end-stage (Espejo-Porras et al., 2015).
Similar to the original hybrid animals, cytoplasmic TDP-43 aggregates were notably absent in motor neurons, despite robust human TDP-43 staining in neuronal nuclei (Hatzipetros et al., 2013). The mice do develop ubiquitinated inclusions in motor neurons of the spinal cord along with astrocytosis in the white matter of the cord (Hatzipetros et al., 2013), a phenotype that is also observed in mice consuming a gel diet (Herdewyn et al., 2014).
Both male and female TARDBP (A315T) mice develop significant motor impairment, with deficits generally appearing earlier in males. Fed a standard diet, males performed poorly on the Rotarod as early as six weeks of age (Dang et al., 2014; Espejo-Porras et al., 2015). Another study found female mice were likewise affected, at least by six months of age (Medina et al., 2014). Male mice showed deficits in the hanging wire test at two to three months of age, but females did not (Hatzipetros et al., 2013). It is important to keep in mind that, especially at later ages, exhaustion and general weakness from GI dysfunction may contribute to a decline in motor performance. Fed a gel diet, both male and female mice developed progressive gait abnormalities culminating at end stage in a “swimming gait” (Herdewyn et al., 2014).
Behaviors associated with learning and memory appear to be largely intact. Males navigated the Y-maze normally at 10 weeks (Dang et al., 2014), and females behaved like non-Tg controls in tests of novel-object recognition and contextual fear learning at six months of age (Medina et al., 2014). However, females displayed deficits in the radial-arm water maze at six months of age, which could not be attributed to differences in swimming speed, suggesting possible deficits in hippocampal-dependent spatial learning (Medina et al., 2014).
TARDBP (A315T) (hybrid) - This is the original hybrid line (C57BL/6J x CBA background), from which the congenic was derived. The hybrid is no longer available.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Lower Motor Neuron Loss
- Cortical Neuron Loss
Cortical Neuron Loss
These mice lose corticospinal tract axons, but outright loss of cortical neurons has not been reported in the model. When crossed with a Thy-1YFP model to label layer 5 pyramidal neurons, mice expressing TDP-43 (A315T) had fewer neurons at 15 weeks of age than YFP littermate controls (Zhang et al., 2016).
Lower Motor Neuron Loss
Most studies reported no lower motor neuron loss. One study observed 20% loss of large ventral horn neurons, possibly dependent on diet and how long the mice live in an individual colony.
Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.
Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.
Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).
Atrophy of gastrocnemius muscle (gel diet).
Deficits have been reported in nonspecific measures of strength and coordination such as the Rotarod (males and females) and hanging-wire test (males). A severely impaired gait (“swimming gait”) was observed in mice fed a gel diet.
Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.
Survival is limited by severe gastrointestinal dysfunction and can be prolonged with a gel diet. Lifespan varies, but in general on a standard diet males live about 3 months and females about 6 months.
Research Models Citations
- 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.
- Hatzipetros T, Bogdanik LP, Tassinari VR, Kidd JD, Moreno AJ, Davis C, Osborne M, Austin A, Vieira FG, Lutz C, Perrin S. C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 2014 Oct 10;1584:59-72. Epub 2013 Oct 18 PubMed.
- Guo Y, Wang Q, Zhang K, An T, Shi P, Li Z, Duan W, Li C. HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice. Brain Res. 2012 Jun 15;1460:88-95. PubMed.
- Herdewyn S, Cirillo C, Van Den Bosch L, Robberecht W, Vanden Berghe P, Van Damme P. Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T) mice. Mol Neurodegener. 2014 Jun 17;9:24. PubMed.
- Esmaeili MA, Panahi M, Yadav S, Hennings L, Kiaei M. Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis. Int J Exp Pathol. 2013 Feb;94(1):56-64. PubMed.
- Zhang W, Zhang L, Liang B, Schroeder D, Zhang ZW, Cox GA, Li Y, Lin DT. Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders. Nat Neurosci. 2016 Apr;19(4):557-9. Epub 2016 Feb 22 PubMed.
- Espejo-Porras F, Piscitelli F, Verde R, Ramos JA, Di Marzo V, de Lago E, Fernández-Ruiz J. Changes in the endocannabinoid signaling system in CNS structures of TDP-43 transgenic mice: relevance for a neuroprotective therapy in TDP-43-related disorders. J Neuroimmune Pharmacol. 2015 Jun;10(2):233-44. Epub 2015 Mar 29 PubMed.
- Dang TN, Lim NK, Grubman A, Li QX, Volitakis I, White AR, Crouch PJ. Increased metal content in the TDP-43(A315T) transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Front Aging Neurosci. 2014;6:15. Epub 2014 Feb 11 PubMed.
- Medina DX, Orr ME, Oddo S. Accumulation of C-terminal fragments of transactive response DNA-binding protein 43 leads to synaptic loss and cognitive deficits in human TDP-43 transgenic mice. Neurobiol Aging. 2014 Jan;35(1):79-87. PubMed.
- Perera ND, Sheean RK, Scott JW, Kemp BE, Horne MK, Turner BJ. Mutant TDP-43 Deregulates AMPK activation by PP2A in ALS models. PLoS One. 2014;9(3):e90449. Epub 2014 Mar 4 PubMed.
- Rojas F, Cortes N, Abarzua S, Dyrda A, van Zundert B. Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress. Front Cell Neurosci. 2014;8:24. Epub 2014 Feb 7 PubMed.
- Walker AK, Soo KY, Sundaramoorthy V, Parakh S, Ma Y, Farg MA, Wallace RH, Crouch PJ, Turner BJ, Horne MK, Atkin JD. ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation. PLoS One. 2013;8(11):e81170. Epub 2013 Nov 29 PubMed.
- Dang TN, Dobson-Stone C, Glaros EN, Kim WS, Hallupp M, Bartley L, Piguet O, Hodges JR, Halliday GM, Double KL, Schofield PR, Crouch PJ, Kwok JB. Endogenous progesterone levels and frontotemporal dementia: modulation of TDP-43 and Tau levels in vitro and treatment of the A315T TARDBP mouse model. Dis Model Mech. 2013 Sep-Oct;6(5):1198-204. PubMed.
- Hebron ML, Lonskaya I, Sharpe K, Weerasinghe PP, Algarzae NK, Shekoyan AR, Moussa CE. Parkin Ubiquitinates Tar-DNA Binding Protein-43 (TDP-43) and Promotes Its Cytosolic Accumulation via Interaction with Histone Deacetylase 6 (HDAC6). J Biol Chem. 2013 Feb 8;288(6):4103-15. PubMed.
- Avendaño-Vázquez SE, Dhir A, Bembich S, Buratti E, Proudfoot N, Baralle FE. Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection. Genes Dev. 2012 Aug 1;26(15):1679-84. PubMed.
- Haidet-Phillips AM, Gross SK, Williams T, Tuteja A, Sherman A, Ko M, Jeong YH, Wong PC, Maragakis NJ. Altered astrocytic expression of TDP-43 does not influence motor neuron survival. Exp Neurol. 2013 Dec;250:250-9. PubMed.