Dataset Information

Methodology Aspects of Colony Maintain for a Murine Model of Amyotrophic Lateral Sclerosis (ALS) TDP-43 Proteinopathy.

ABSTRACT: The use of genetically engineered mouse (GEMs) models provides an unprecedented opportunity to study the genetic basis of diseases and gene function, therefore it is paramount to determine reproductive parameters that guarantee proper colony maintenance. We studied the reproductive parameters of mice hemizygous for TDP-43^A315T transgene, which are viable, fertile, and express a mutant human TAR DNA binding protein (hTDP-43) cDNA harboring an amino acid substitution associated with familial amyotrophic lateral sclerosis (fALS). TDP43^A315T mice were backcrossed to a C57Bl6/J pure background for four consecutive generations. The Tg offspring genotype were then confirmed by PCR assays. Our statistical analysis indicated there were no differences in the sex and number of pups per offspring when hemizygous female and male TDP43^A315T mice were backcrossed to C57Bl6/J mice. Interestingly, our results showed significant differences in the number of offspring expressing the transgene when hemizygous TDP43^A315T male mice were used as breeders. Therefore, our findings suggest that male TDP43^A315T mice transfer the transgene with a greater genetic strengths. Such is an important breeding consideration to ensure the principle of reduction in animal experimentation considering most basic research with models focuses on males and excludes female mice.

SUBMITTER: Alvaro-Alonso C

PROVIDER: S-EPMC7762410 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Methodology Aspects of Colony Maintain for a Murine Model of Amyotrophic Lateral Sclerosis (ALS) TDP-43 Proteinopathy.

Álvaro-Alonso César C Ferrer-Donato Águeda Á Fernández-Torres Elizabeth E Carballo-Villa Mónica M Fernandez-Martos Carmen M CM

Animals : an open access journal from MDPI 20201207 12

The use of genetically engineered mouse (GEMs) models provides an unprecedented opportunity to study the genetic basis of diseases and gene function, therefore it is paramount to determine reproductive parameters that guarantee proper colony maintenance. We studied the reproductive parameters of mice hemizygous for TDP-43<sup>A315T</sup> transgene, which are viable, fertile, and express a mutant human TAR DNA binding protein (hTDP-43) cDNA harboring an amino acid substitution associated with fam ...[more]

PMID: 33297584

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Project description:Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is considered to have prion-like properties. Historical studies have predominantly focused on genetic forms of ALS, which represent ?10% of cases, leaving the remaining 90% of sporadic ALS relatively understudied. Additionally, the role of astrocytes in ALS and their relationship with TDP-43 pathology is also not currently well understood. We have therefore used highly enriched human induced pluripotent stem cell (iPSC)-derived motor neurons and astrocytes to model early cell type-specific features of sporadic ALS. We first demonstrate seeded aggregation of TDP-43 by exposing human iPSC-derived motor neurons to serially passaged sporadic ALS post-mortem tissue (spALS) extracts. Next, we show that human iPSC-derived motor neurons are more vulnerable to TDP-43 aggregation and toxicity compared with their astrocyte counterparts. We demonstrate that these TDP-43 aggregates can more readily propagate from motor neurons into astrocytes in co-culture paradigms. We next found that astrocytes are neuroprotective to seeded aggregation within motor neurons by reducing (mislocalized) cytoplasmic TDP-43, TDP-43 aggregation and cell toxicity. Furthermore, we detected TDP-43 oligomers in these spALS spinal cord extracts, and as such demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this observed cell-type specific toxicity, providing further support to a protein oligomer-mediated toxicity hypothesis in ALS. In summary, we have developed a human, clinically relevant, and cell-type specific modelling platform that recapitulates key aspects of sporadic ALS and uncovers both an initial neuroprotective role for astrocytes and the cell type-specific toxic effect of TDP-43 oligomers.

Dataset Information

Methodology Aspects of Colony Maintain for a Murine Model of Amyotrophic Lateral Sclerosis (ALS) TDP-43 Proteinopathy.

Publications

Methodology Aspects of Colony Maintain for a Murine Model of Amyotrophic Lateral Sclerosis (ALS) TDP-43 Proteinopathy.

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