Herman B. Fernandes, Jose Beltran, Mei Kwan, John Shea, Daniel Havas, Afshin Ghavami, Taleen Hanania
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease characterized by specific cell death of the upper and/or lower motor neurons. The decline in neuromuscular transmission leads to muscle weakness and in some cases, paralysis. One of the underlying pathologies in ALS is the presence of TAR DNA-binding protein of 43 kDA (TDP-43) in the brain and spinal cord. Bigenic TDP-43ΔNLS mice were generated by crossing transgenic mice expressing tTA under the control of the human neurofilament heavy chain (NEFH) promoter with tetO-hTDP-43ΔNLS mice having a defective nuclear localization motif (ΔNLS; Walker et al, 2015). Doxycycline (DOX) suppresses expression of hTDP-43ΔNLS gene, thereby rescuing the disease phenotype. Bigenic TDP-43ΔNLS mice show a progressive loss of body weight, grip strength, deficits in rotarod performance, increased tremors and hindlimb clasping, impaired gait and decreased survival compared to tTA control mice. Assessment of compound muscle action potentials (CMAP) found that TDP-43ΔNLS exhibited an increase in the latency of muscular response and decreased response amplitudes of muscle contractions following motor nerve stimulation. Treatment with DOX attenuated the behavioral and CMAP deficits. CSF and plasma neurofilament light chain (NF-L) levels are elevated in TDP-43ΔNLS mice in an age-dependent manner. Additionally, these mice show increased inflammatory markers in the brain. Treatment with DOX attenuated the elevation in both NF-L level and inflammatory marker mRNA expression. Immunohistochemical analysis of TDP-43 pathologies revealed strong overexpression of TDP-43 in perinuclear cytoplasmic inclusions, accompanied by deposition of pTDP43 aggregates in multiple brain regions. Additionally, astrogliosis and microglial activation were seen. Similar pathologies were detected in spinal cord but were less severe compared to brain. This model recapitulates the deregulated translocation of TDP-43 from the nucleus to the cytoplasm, a major pathology seen in ALS patients and provides a preclinical model for screening novel therapeutics.