TDP-43 Mouse Model of Amyotrophic Lateral Sclerosis (ALS)

TDP-43 Model Overview

Cytoplasmic TDP-43 (or TDP43) aggregates are a hallmark of familial and sporadic ALS. While several transgenic (tg) mouse models of amyotrophic lateral sclerosis (ALS; also called motor neuron disease [MND]) with TDP-43 aggregation exist, they each have their respective strengths and weaknesses. Learn more about animal models of ALS in our Resource - ALS Mouse Models for Drug Development.

At Biospective, we use both the original and modified versions of the rNLS8 (or ΔNLS; delta NLS; dNLS) ALS mouse model of TDP-43 proteinopathy ("TDP-43 models"): 

• Original mouse model ("Off Dox"): rapidly progressing (weeks)
• Biospective mouse model ("Low Dox"): slower progressing (months)

Significant advantages of these TDP-43 models for ALS researchers include:

• Mislocalization of TDP-43 to the cytoplasm
• Progressive motor deficits
• Motor neuron degeneration & regional brain atrophy
• Neuroinflammation
• Brain, spinal cord, and neuromuscular junction pathology

The model time course is predictable and the measures of disease progression are highly reproducible, making it an excellent model for the evaluation of therapeutic agents in preclinical studies. Learn more in our Resource - TDP-43 ΔNLS (rNLS8) Mice for Drug Development.

TDP-43 Mice Generation

rNLS8 (NEFH-hTDP-43-ΔNLS) double transgenic ALS mice ("TDP43 mouse model") are generated by breeding mice having the NEFH-tTA transgene with mice having the tetO-hTDP-43-ΔNLS transgene. This TARDBP model was originally developed and reported by Walker et al. (Acta. Neuropathol., 130: 643-670, 2015). It is a model of amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND). It can also be used as a TDP-43 pathology model of frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD).

These TDP-43 transgenic 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.

Our Validated TDP-43 Transgenic Mice Measures

• Body weight
• Motor scoring (hindlimb clasping, tremor, grill agility, paralysis)
• Grip strength test
• In vivo muscle electrophysiology, including Compound Muscle Action Potential (CMAP) (see ALS Mouse Models & Spinal Motor Neurons)
• Muscle atrophy measured by longitudinal, in vivo computerized tomography (CT) (see TDP-43 ΔNLS (rNLS8) Mice for ALS Drug Development)
• Neurofilament light chain measures in plasma & CSF
• MRI brain atrophy to measure neurodegeneration (Read More in our Presentation - Brain Atrophy Analysis in Mouse Models of Neurodegeneration)
• Immunohistochemistry & multiplex immunofluorescence