Overall, our data indicate that spinal cord-specific increase of TDP-43 (N390D), due in part to its higher stability, and the associated of gain-of-toxicity in Bcl-2 pre-mRNA splicing are among the essential early causative events of ALS pathogenesis of the TDP-43 (N390D/+) mice. The gene discussed is BCL2; the disease is amyotrophic lateral sclerosis.