Amyotrophic lateral sclerosis (ALS) is a progressive, incurable disease that causes loss of muscle mass throughout the body due to degeneration of motor neurons. TDP-43 is a key protein of ALS, but it is not well understood how abnormalities of TDP-43 cause motor neuron dysfunction and cell death. In this study, we will investigate the pathomechanisms of ALS at different stages, including protein, cell, brain and spinal cord, and systemic stages, using newly developed animal models and blood samples from patients, in order to understand the root causes of the disease and to develop treatments.