Premature death of <scp>TDP</scp>‐43 (<scp>A</scp>315<scp>T</scp>) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis

Esmaeili, Mohammad Ali; Panahi, Marzieh; Yadav, Shilpi; Hennings, Leah; Kiaei, Mahmoud

doi:10.1111/iep.12006

Cited by 75 publications

(67 citation statements)

References 37 publications

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“…We observed a sexual dimorphism in disease onset and survival of TDP-43 (A315T) mice, as reported previously [19]. Male mice had a median survival of 84 days, whereas females survived for 126 days (Figure 1A).…”

Section: Resultssupporting

confidence: 88%

Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T)mice

Herdewyn

Cirillo

Bosch

et al. 2014

Mol Neurodegeneration

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BackgroundIntraneuronal inclusions of TAR DNA-binding protein 43 (TDP-43) have been found in the majority of Amyotrophic Lateral Sclerosis (ALS) patients. Mutations in the gene encoding TDP-43 cause familial ALS. Transgenic mice expressing mutant TDP-43 with one such mutation (TDP-43 (A315T)) under control of the murine prion promoter develop motor symptoms, but their use is currently hampered by sudden death. We aimed to understand and overcome the cause of sudden death in TDP-43 (A315T) mice. Since intestinal obstruction was suspected to be the cause, intestinal motility of TDP-43 (A315T) mice was studied in an ex-vivo pellet propulsion assay. The effect on the enteric and motor phenotype was assessed, both in animals on normal chow or on a jellified fiber deprived diet, aimed at preventing intestinal obstruction.ResultsThe frequency of the propulsive motor complexes was significantly reduced in the colon of TDP-43 (A315T) compared to non transgenic (NTG) mice. Immunohistochemistry revealed significant enlargement in size and reduction in number of the nitric oxide synthase (NOS) neurons in the myenteric plexus of TDP-43 (A315T) mice. Prevention of intestinal obstruction by jellified food abolished sudden death, allowing the motor phenotype to develop and slowly progress with a more pronounced degeneration of upper and lower motor axons. A downregulation of endogenous TDP-43 mRNA and protein levels was observed prior to neurodegeneration.ConclusionTDP-43 (A315T) mice suffer from intestinal dysmotility due to degeneration of NOS neurons in the myenteric plexus. Feeding the mice jellified food prevents sudden death and allows the motor phenotype to progress.

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Section: Resultssupporting

confidence: 88%

Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T)mice

Herdewyn

Cirillo

Bosch

et al. 2014

Mol Neurodegeneration

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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: 99%

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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“…A number of TDP-43 transgenic mouse models have been generated to study the pathogenesis of FTD and ALS. One model, in which the mouse prion promoter drives expression of the Ala315Thr mutant form of TDP-43 (Prp-TDP43 Ala315Thr ) 129 , causes symptoms of intestinal obstruction followed by sudden death 130,131 . Enteric neurons and glia normally express TDP-43 and the mouse prion promoter is active in both cell types 132 .…”

Section: Primary Disorders Of the Cnsmentioning

confidence: 99%

The bowel and beyond: the enteric nervous system in neurological disorders

Rao

Gershon

2016

Nat Rev Gastroenterol Hepatol

488

362

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The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS). An intact ENS is essential for life and ENS dysfunction is often linked to digestive disorders. The part the ENS plays in neurological disorders, as a portal or participant, has also become increasingly evident. ENS structure and neurochemistry resemble that of the CNS, therefore pathogenic mechanisms that give rise to CNS disorders might also lead to ENS dysfunction, and nerves that interconnect the ENS and CNS can be conduits for disease spread. We review evidence for ENS dysfunction in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease. Animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions. Moreover, the neurotropic pathogen, varicella zoster virus (VZV), unexpectedly establishes latency in enteric and other autonomic neurons that do not innervate skin. VZV reactivation in these neurons produces no rash and is therefore a clandestine cause of gastrointestinal disease, meningitis and strokes. The gut–brain alliance has raised consciousness as a contributor to health, but a gut–brain axis that contributes to disease merits equal attention.

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Premature death of TDP‐43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis

Cited by 75 publications

References 37 publications

Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T)mice

Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T)mice

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

The bowel and beyond: the enteric nervous system in neurological disorders

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