Grant: Operating Grant

ALS is an adult-onset neurodegenerative disorder characterized by the progressive degeneration of motor neurons in the brain and spinal cord. TDP-43 is a protein detected in pathological aggregates motor neurons of ALS cases and a role for TDP-43 in disease was further supported by the discovery of TDP-43 mutations in familial ALS cases. The physiological role of TDP-43 and the pathogenic pathways of TDP-43 abnormalities are not well understood. Recently, our group generated novel TDP-43 transgenic mice that mimic several features of human ALS. Here we propose to take advantage of these unique ALS mouse models to investigate pathogenic pathways associated with TDP-43 abnormalities and to test new therapeutic approaches. First, we will test whether TDP-43 abnormalities in transgenic mice is associated with misfolding of superoxide dismutase (SOD1). Second, we recently discovered that TDP-43 upregulation can enhance activity of a specific pathway involved in innate immune responses. We propose to clarify what factors trigger this pathway during aging and in what cell types this pathway contributes the most to pathogenesis in TDP-43 transgenic mice. The new TDP-43 mouse models of ALS will also be used to test new therapeutic approaches based on inhibition of this pathogenic pathway.