Objective: Transactive response-DNA binding proteinopathy (TDP-43) has become a hallmark feature in motor neuron diseases. Not only overexpression, but also deletion of the nuclear localization signal (NLS) causes proteinopathic alterations. We employed viral vector mediated gene transfer method for delivery of genes encoding native or mutant TDP-43 to assess motor functions of young adult male and female Sprague-Dawley rats.
Methods: Motor neuron specific targeting of AAV9 vectors were achieved by using a cell type specific promoter (UCHL1). While control animals received SF injection (n=10), experimental groups were injected by either native or NLS-deleted viruses (1.77×1012 vg/kg, n=7/each group), on postnatal day 30. Following systemic injection of viruses, motor coordination of animals was evaluated by Rota-rod and modified grip tests for 4 weeks. Then, spatial learning and memory abilities of animals were measured by Morris Water Maze (MWM) test.
Results: The number of falls from the rota-rod apparatus was significantly higher in males injected by native TDP-43 than those of controls at 4th week (p<0.05). Grip test scores of females showed no difference between the control and experimental groups. In contrast, scores of the males in the experimental groups were significantly lower (p<0.01) than those of controls. MWM results displayed no significant difference between control and experimental groups in terms of latency to reach the platform and time spent in the target quadrant.
Conclusion: Transduction of animals with native or NLSdeleted TDP43 gene sequences results in gender-biased changes in motor functioning and disease onset without cognitive impairments. This relatively low cost, novel model might be helpful in testing therapeutic approaches in motor neuron diseases. This study is supported by TÜB‹TAK-Grant #116S408.