| Summary: | Background: Motor neurone disease (MND) is a fatal, progressive, neurodegenerative disease causing muscle weakness, spasticity and paralysis. No small molecule drugs have translated from MND mouse models to MND patients, possibly because of MND mouse models being based on SOD1 mutations, representing only a small proportion of patients. Nearly all non-SOD1 patients have TDP-43 pathology, whereas SOD1 patients do not, suggesting a mechanistic difference between non-SOD1 and SOD1-related MND. A TDP-43 model may be more representative of the patient population and lead to better translation of treatments. There is also a need for translational biomarkers in MND to further improve translation. Methods: A colony of mice transgenic for mutant human TDP-43 (TDP-43Q331K) was established, alongside a control line (TDP-43WT). The mice were characterised for motor function including rotarod, gait analysis, and neuroscoring. Immunohistochemical, mRNA and protein level studies were also carried out. Increased weight was noted in the TDP-43Q331K mice, leading to a study of voluntary activity and food intake. A further study investigated electrophysiological parameters, apathy, and riluzole treatment. Preclinical 31P-MRS imaging was carried out in SOD1G93A mice in an attempt to find a translational biomarker. Results: TDP-43Q331K mice developed a progressive phenotype, whilst TDP-43WT mice showed none. TDP-43Q331K mice showed signs of motor dysfunction, increased TDP-43 in the nucleus and cytoplasm of motor neurons (supported by increased mRNA and protein levels), astrogliosis, and microgliosis in the spinal cord, apathy, overeating and electrophysiological findings suggestive of denervation. Riluzole may have had a mild treatment effect in TDP-43Q331K mice, measured by electrophysiology. No conclusions could be drawn from the preclinical 31P-MRS due to animal welfare issues. Conclusions: TDP-43Q331K mice have a progressive motor phenotype of low variability with reliable motor, pathological and cognitive readouts of disease and may provide a useful model for evaluating potential neuroprotective therapies.
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