The ALS-inducing factors, TDP43(A315T) and SOD1(G93A), directly affect and sensitize sensory neurons to stress

There is increased recognition that sensory neurons located in dorsal root ganglia (DRG) are affected in amyotrophic lateral sclerosis (ALS). However, it remains unknown whether ALS-inducing factors, other than mutant superoxide dismutase 1 (SOD1(G93A)), directly affect sensory neurons. Here, we examined the effect of mutant TAR DNA-binding protein 1 (TDP43(A315T)) on sensory neurons in culture and in vivo. In parallel, we reevaluated sensory neurons expressing SOD1(G93A). We found that cultured sensory neurons harboring either TDP43(A315T) or SOD1(G93A) grow neurites at a slower rate and elaborate fewer neuritic branches compared to control neurons. The presence of either ALS-causing mutant gene also sensitizes sensory neurons to vincristine, a microtubule inhibitor that causes axonal degeneration. Interestingly, these experiments revealed that cultured sensory neurons harboring TDP43(A315T) elaborate shorter and less complex neurites, and are more sensitive to vincristine compared to controls and to SOD1(G93A) expressing sensory neurons. Additionally, levels of two molecules involved in stress responses, ATF3 and PERK are significantly different between sensory neurons harboring TDP43(A315T) to those with SOD1(G93A) in vitro and in vivo. These findings demonstrate that sensory neurons are directly affected by two ALS-inducing factors, suggesting important roles for this neuronal subpopulation in ALS-related pathogenesis.