Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by the destruction of the motor neurons. It usually affects people between 40 and 60-year-old and the average survival from onset to death is 3–4 years. Despite the severity of the disease and the high health care and social costs, no cure or viable long-term effective treatment has been identified. Moreover, the failure to translate positive preclinical results from the SOD1 mouse model into clinical efficacy has raised questions about the translational suitability of this model. For this reason, the TDP-43 transgenic mouse model was created by overexpressing the mutant human TDP-43 gene, mutation directly related with ALS. In this study we characterized this mouse strain TDP-43, recognized as a preclinical mouse model for ALS disorder. We observed neuromuscular disorders, peripheral nerve electrophysiological impairment and histological anomalies at 3 months old. We also demonstrated that intrathecal injection of AAV1 expressing shRNA for casein kinase-1d (CK1d) attenuated the peripheral degenerative phenotype in this ALS model. Our data confirm that TDP-43 mouse strain is a robust and reproducible model to analyze the neuropathy disorders of ALS and that gene therapy silencing CK1d is a promising therapy for human ALS disorder, and can be used as a positive reference control for additional new drugs efficacy studies targeting ALS.