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TDP-43 Transgenic Models

Our TDP-43 mouse models demonstrate cytoplasmic aggregates, motor dysfunction, neurodegeneration, and neuromuscular changes.

Model Overview

Cytoplasmic TDP-43 aggregates are a hallmark of ALS. While several transgenic models of TDP-43 pathology exist, they each have their respective strengths and weaknesses.

At Biospective, we use both the original and modified versions of the rNLS8 (or ΔNLS) model originally developed at the University of Pennsylvania (in-licensed by Biospective). 

  • Original model ("Off Dox"): rapid progressing (weeks)
  • Biospective-modified model ("Low Dox"): slower progressing (months)

Significant advantages of this model include

  • Mislocalization of TDP-43 to the cytoplasm
  • Motor deficits
  • Neurodegeneration & regional brain atrophy
  • Brain, spinal cord, and neuromuscular junction pathology

The model time course is predictable and the measures are highly reproducible.

Our Validated Measures

  • Body weight
  • Motor scoring (clasping, grill agility, paralysis, tremor)
  • Grip strength test & wire hang test
  • MRI brain atrophy (Read More in our Presentation - Brain atrophy analysis in rodent models of neurodegenerative diseases)
  • In vivo muscle electrophysiology (CMAP & MUNE)
  • Neurofilament Light (NfL) measures in plasma & CSF
  • Immunohistochemistry & multiplex immunofluorescence

Learn more about our characterization of this model and our validated measures.


What is the rNLS8 (ΔNLS) model?

rNLS8 (NEFH-hTDP-43-ΔNLS) double transgenic mice are generated by breeding mice having the NEFH-tTA transgene with mice having the tetO-hTDP-43-ΔNLS transgene. The model was originally developed and reported by Walker et al. (Acta. Neuropathol., 130: 643-670, 2015; doi: 10.1007/s00401-015-1460-x).

Mice are maintained on a Dox diet during breeding and the initial aging period (typically 5 to 12 weeks-of-age). The mice are then changed from a Dox diet to a standard diet ("Off Dox" model) or an alternate protocol developed by Biospective ("Low Dox" model) to allow for human TDP-43 expression. An interesting feature of this model is that pathologic and functional recovery can be achieved by putting mice back on a Dox diet.

Has disease-modification been shown in the TDP-43 transgenic model?

Yes. Here is a nice example:
Young, P.R., DeDuck, K., Bedell, B.J. AIT-101 improves functional deficits in a human TDP-43 animal model of ALS. 22nd Annual Meeting of the Northeast ALS Consortium, 2023; doi:10.1002/mus.27969

What is a "nuclear localization signal"?

A nuclear localization signal (NLS) is typically a short peptide which facilitates the transport of a protein from the cytoplasm into the nucleus of a cell. A review can be found at doi:10.1186/s12964-021-00741-y.

What is the advantage of Biospective's "Low Dox" model over the conventional model?

The standard rNLS8 model is a rapidly progressing model. While this model is very useful, we have found that most of our Sponsors want a less severe, slower progressing model to increase the opportunity to observe a drug effect. The Low Dox model shows a similar phenotype to the standard model, but evolves over a longer period of time.

Are phosphorylated TDP-43 aggregates seen in the TDP-43 transgenic model?


Yes. We have developed excellent immunohistochemistry (IHC) and immunofluorescence (IF) protocols that nicely demonstrated "punctate" p-TDP-43 (p409/410) aggregates in the cytoplasm of neurons.




What type of therapeutic agents has Biospective evaluated in the TDP-43 transgenic model?

We tested a wide range of therapeutic agents, including antibodies, gene therapy, small molecules, and peptides using a variety of different routes of administration.

Can Biospective perform oral dosing in the TDP-43 transgenic model?

Yes. We routinely perform oral gavage of pharmacological agents in this model. We can also deliver via food or drinking water.

How long are Biospective's studies involving the "Low Dox" model?

Typical in-life study durations range from 3-12 weeks. We can work with you to define the optimal duration based on your particular therapeutic agent.

Are mice readily available for studies?

Yes. We maintain a well-established breeding colony of the mice so that they are readily available for studies. We would be happy to discuss study timelines with you.

More Information

Let us know what you’re interested in. Our team will be happy to discuss with you!

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