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TDP-43 Transgenic Models

Cytoplasmic TDP-43 (TDP43; TARDBP) aggregates are a hallmark of familial and sporadic Amyotrophic Lateral Sclerosis (ALS). We provide a range of services using the transgenic rNLS8 (or ΔNLS; delta NLS; dNLS) ALS model of TDP-43 proteinopathy ("TDP-43 models"). Our studies with these ALS mice use either the original mouse model ("Off Dox"), which shows rapid progression over several weeks, or an alternative, slower progressing ("Low Dox") version developed by Biospective.

Both the Off Dox and Low Dox models have mislocalization of TDP-43 aggregates to the cytoplasm, progressive motor deficits, motor neuron degeneration & regional brain atrophy, neuroinflammation (activated microglia & reactive astrocytes), muscle atrophy & altered CMAP, as well as brain, spinal cord, & neuromuscular junction pathology.

Microscopic view of a tissue sample stained to highlight the presence of phosphorylated TDP-43 (pTDP-43) protein

Learn more about our characterization of these ALS mouse models, our validated measures, and our Preclinical Neuroscience CRO services.

FAQs

What is the rNLS8 ALS mouse model?

The "regulatable" NLS model is also known as the TDP-43 ΔNLS model. It is a double transgenic mouse originally reported by Walker and colleagues in 2015. It is considered regulatable since the expression of the TDP-43 ΔNLS transgene (under the NEFH promoter) can be controlled via the administration of the tetracycline-analog doxycycline (Dox). The TDP-43 ΔNLS transgene expression is suppressed during administration of a high dose of Dox. You can learn more about this model in our Resource - TDP-43 ΔNLS (rNLS8) Mice for Drug Development.

What is Biospective's "Low Dox" model?

The conventional protocol for disease induction in rNLS8 mice involved the simple replacement of diet containing doxycycline (Dox) with a standard diet to generate a rapidly progressing model (Walker, 2015). While this model is very useful, we have found that many of our Sponsors want a less aggressive, slower progressing model to increase the opportunity to observe a drug effect in preclinical therapeutic efficacy studies. As such, we developed an alternate ("Low Dox") protocol where these mice show a similar phenotype to the standard model, including neurodegeneration, but the disease progression evolves over a longer period of time.

What are the typical readouts that you use in TDP-43 mouse model studies?

We have a large range of measures available. Standard readouts/endpoints include:

  • Body weight
  • Motor scoring (hindlimb clasping, grill agility, tremor, paralysis)
  • Grip strength test
  • MRI brain atrophy to measure neurodegeneration
  • In vivo muscle electrophysiology, including Compound Muscle Action Potential (CMAP)
  • Muscle atrophy measured by computerized tomography (CT)
  • Neurofilament light chain measures in plasma & CSF
  • Immunohistochemistry & multiplex immunofluorescence

Is neurofilament light chain (NfL; NF-L) elevated in the blood or CSF of TDP-43 mice?

Yes. We see significant elevations of NfL levels in both the plasma and CSF from these mice using the Simoa assay. NfL levels serve as a robust, clinically translational biomarker of axonal injury and axon degeneration and complement other quantitative markers of neurodegeneration, such as MRI brain atrophy.

Related Content

Up-to-date information on ALS and best practices related to the evaluation of therapeutic agents in ALS animal models.

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