TDP-43 pathology underlies 97% of all ALS cases, making the TDP-43(Q331K) transgenic mouse a clinically relevant preclinical tool. Presented at SfN Neuroscience 2025 in San Diego, this poster provides longitudinal phenotypic characterization of female TDP-43(Q331K) mice from 4 weeks to 8 months of age.

Elevated plasma neurofilament light chain (NfL) was detected as early as 5 weeks of age, preceding overt motor symptoms and confirming early neuronal injury. Compound muscle action potential (CMAP) reductions confirmed peripheral motor axon loss from 7 weeks. Progressive deficits spanning rotarod, inverted grid, weightlifting, and CatWalk gait analysis were observed across all timepoints, with the most pronounced phenotype at 8 months. These data support the TDP-43(Q331K) model as a suitable preclinical platform for evaluating disease-modifying therapies in ALS and frontotemporal dementia (FTD).

TAR DNA binding protein 43 (TDP-43), encoded by the TARDBP gene, is a major pathological protein in ALS and FTD, present in 97% of all ALS cases. In this study, we performed extensive longitudinal characterization of TDP-43 Q331K mice to assess progression of disease-relevant phenotypes and model suitability for preclinical therapeutic efficacy studies. 

Transgenic female TDP-43 mice expressing human TDP-43 with the Q331K mutation (JAX #017933) and wildtype controls were examined at early timepoints (4, 7, 10, and 13 weeks) and older ages (4, 6, and 8 months). Motor function was assessed using automated home-cage monitoring, inverted grid, weight-lifting, rotarod, CatWalk gait analysis, and grip strength. Nerve conduction was assessed by compound muscle action potential (CMAP) recording. Blood was collected for plasma NfL analysis and tissues for histopathology. 

Plasma NfL was significantly elevated from 5 weeks, indicating early-onset progressive neuronal injury before overt behavioral deficits. CMAP amplitude was significantly reduced from 7 weeks, reflecting functional motor axon loss. Rotarod performance declined progressively and CatWalk gait analysis revealed worsening across all five major parameter groups — temporal, spatial, run, interlimb coordination, and kinetic. Principal component analysis confirmed consistent, progressive phenotype aggravation, with the most pronounced phenotype at 8 months. 

The motor and biomarker profile of TDP-43 Q331K mice closely mirrors the human course of ALS pathophysiology, supporting this model for preclinical efficacy studies targeting ALS and FTD.