C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS

Hatzipetros, Theo; Bogdanik, Laurent; Tassinari, Valerie R.; Kidd, Joshua D.; Moreno, Andy J.; Davis, Crystal; Osborne, Melissa; Austin, Andrew D.; Vieira, Fernando; Lutz, Cathleen; Perrin, Steve

doi:10.1016/j.brainres.2013.10.013

Cited by 92 publications

(89 citation statements)

References 33 publications

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“…Apart from expression levels, the differences in survival between TDP-43 transgenic lines may further be attributed to different promoters used for expression [21,37,46], or genetic backgrounds used [5]. Furthermore, reduced survival of mutant TDP-43 transgenic mice driven by the prion promoter has been linked to bowel paralysis [11,14,16].…”

Section: Discussionmentioning

confidence: 92%

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Hummel

Stevens³

et al. 2015

Acta Neuropathol

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The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.

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Section: Discussionmentioning

confidence: 92%

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Hummel

Stevens³

et al. 2015

Acta Neuropathol

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“…A link between the motor system and the ENS has been found in a mouse model, where lack of GDNF (glial cell line-derived neurotrophic factor - a potent protective factor for motor neurones) leads to considerable loss of ENS neurones [89], while the receptor tyrosine kinase Ret (c-Ret), which transduces GDNF signalling, is highly expressed by a specific subtype of enteric neurons in the human ENS [90]. Furthermore, the TDP-43 mouse model of ALS exhibits intestinal dysfunction characterized by a progressively thinned colon, swollen small intestine, reduced food intake, and increased TDP-43 accumulation in the myenteric nerve plexus, which contributes to death independent of muscular weakness [91,92]. In addition to animal models of ALS manifesting abnormalities of the gut, autonomic dysfunction has been described in ALS patients [44], with reports of subclinical gastrointestinal motor dysfunction [43], delayed colonic transit times [93], delayed gastric emptying [94], and an increased prevalence of constipation [95].…”

Section: Meeting Energy Needs In Alsmentioning

confidence: 99%

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research.

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“…Other genetic backgrounds have also been shown to influence survival in these mice, and gene identification is underway [28]. Recent studies also demonstrated that survival of the transgenic mouse (Prnp-TARDBP*A315T)95Balo/J was also influenced by genetic background [29]. In a dominant modifier screen, male survival was significantly different across a number of F1 genetic crosses and, in addition, males were always significantly more affected than females, regardless of genetic background, giving this mouse model both gender-specific and genetic background-specific influences [29].…”

Section: Leveraging Technologies To Explore Genetic Modifiersmentioning

confidence: 99%

“…Recent studies also demonstrated that survival of the transgenic mouse (Prnp-TARDBP*A315T)95Balo/J was also influenced by genetic background [29]. In a dominant modifier screen, male survival was significantly different across a number of F1 genetic crosses and, in addition, males were always significantly more affected than females, regardless of genetic background, giving this mouse model both gender-specific and genetic background-specific influences [29]. Advances in high-throughput exome sequencing will significantly enhance our ability to identify these genetic modifiers, even in complex genetic interactions.…”

Section: Leveraging Technologies To Explore Genetic Modifiersmentioning

confidence: 99%

Optimizing Mouse Models of Neurodegenerative Disorders: Are Therapeutics In Sight?

Lutz

Osborne

2013

Future Neurol.

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The genomic and biologic conservation between mice and humans, along with our increasing ability to manipulate the mouse genome, places the mouse as a premier model for deciphering disease mechanisms and testing potential new therapies. Despite these advantages, mouse models of neurodegenerative disease are sometimes difficult to generate and can present challenges that must be carefully addressed when used for preclinical studies. For those models that do exist, the standardization and optimization of the models is a critical step in ensuring success in both basic research and preclinical use. This review looks back on the history of model development for neurodegenerative diseases and highlights the key strategies that have been learned in order to improve the design, development and use of mouse models in the study of neurodegenerative disease.

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C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS

Cited by 92 publications

References 33 publications

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

Optimizing Mouse Models of Neurodegenerative Disorders: Are Therapeutics In Sight?

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