Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motoneurons. This leads to brain degeneration and muscle denervation, resulting in extensive muscle atrophy and functional motor impairments. TAR DNA binding protein 43 (TDP-43) encoded by the TARDBP gene, is a major pathological protein involved in the pathogenesis of ALS (TDP-43 pathology is observed in 97% of ALS patients) and frontotemporal dementia (FTD). In this newsletter, we show that the motor deficits in human transgenic TDP-43 mouse model (TDP-43Q331K) closely reflect the human course of ALS pathophysiology, indicating its suitability for preclinical efficacy studies 

TDP-43Q331K mice show reduced compound muscle action potential (CMAP) in the nerve conduction test  

Whisker box plots showing differences in nerve conduction CMAP between transgenic TDP-43 mouse model and WT TDP-43 mouse model.

FIGURE 1. TDP43Q331K mice show progressive worsening of neuromuscular function. Reduction of compound muscle action potential (CMAP) amplitude was seen in TDP-43 mice, reflecting loss of functional motor axons as observed in ALS patients. Data from multiple batches were normalized to the mean of the respective WT group. 

TDP-43Q331K mice show elevated plasma neurofilament light chain (NfL) protein concentrations 

Whisker and bar plot showing plasma neurofilament protein conentrations in a transgenic TDP-43 mouse model.

FIGURE 2. Neurofilament light chain (NfL) levels in the plasma of human TDP-43Q331K transgenic mice. Compared to WT littermates, TDP-43 mice show significantly higher concentrations of plasma NfL at 7 months (the first measured timepoint) and 9 months of age. Increasing NfL in blood (and CSF) is a marker of neuronal injury, confirming the extensive neurodegenerative phenotype observed in ALS mice.  

TDP-43Q331K mice show progressive deficits in motor function  

Line graphs showing progressive decrease in motor function of transgenic TDP-43 mouse model compared to wild type TDP-43 mice.

FIGURE 3. TDP43Q331K mice show progressive worsening of neurodegenerative disease phenotype over time marked by motor function deficits. Compared to WT littermates, TDP43Q331K mice show (A) progressive motor deficits (Rotarod) and (B) reduced muscle function (Weightlifting test). Further motor impairments in TDP-43 mice were assessed in automated home-cages (PhenoTyperTM). (C) Compared to WT littermates, TDP-43 mice are significantly less active during the dark phase and (D) spend significantly less time climbing on top of the shelter (OnShelter zone) during the dark phase up until 8 months of age.  

Figures showing gait analysis parameters in transgenic TDP-43 mouse model.

FIGURE 4. TDP43-Q331K mice walk abnormally in the CatWalk Gait Analysis. (A) In TDP-43 mice, the significant deficits in locomotor parameters reflect the degree of motor weakness allowing for an assessment of disease progression and prediction of disease severity. (B-C) Female TDP43Q331K mice show progressive worsening of walking patterns in all 5 major parameter groups (only two shown): temporal, spatial, run, interlimb coordination, and kinetic. Click here to view a video comparison of WT and TDP43 mice walking on the CatWalkTM gait analysis platform.   

Principal component analysis (PCA) reveals consistent progression of the neurodegenerative phenotype of TDP-43 ALS mice 

PCA is a statistical approach that we commonly use at InnoSer when dealing with large datasets especially relating to a mouse model phenotype. PCA finds similarities or correlations of parameters in a large data matrix and combines the parameters in orthogonal variables called principal components (PCs). These correlations are controlled for quality and return a matrix of eigenvalues which represent the importance of each PC, and in turn the amount of explained variation found in the data 

Bubble plot showing principle component analysis (PCA) results of ALS models.

FIGURE 5. PCA bubble plot shows comparison of the progressive age-related neurodegenerative phenotype between 2 ALS mouse models (SOD1*G93A and TDP43). SOD1 ALS models (both males and females; red bubbles) were tested at 1.5, 3 and 5M of age. While the 1.5M group showed small deviation vs control (center 0 point of the plot), the 3M groups showed a large deviation, with consistent results in 2 different SOD1 backgrounds (B6/J and B6SJL/J). At 5M, SOD1 model reached humane endpoint by paralysis symptoms, resulting in a bubble in different direction from the 1.5M and 3M. TDP43 ALS mice (females; green bubbles) were tested at 4, 6 and 8M of age. The bubbles moved gradually further away from the center in the same quadrant, indicating the phenotype aggravated consistently in the same direction in this model, with ALS mice at 8M showing the most pronounced phenotype  

Interested in performing efficacy studies using InnoSer’s TDP-43 mouse model? Consulting with our neurology study experts will allow you to carry out tailored studies while collecting the most study-appropriate data.  Contact us to inquire about performing a study in the TDP-43 mouse model.