The ALS-inducing factors, TDP43A315T and SOD1G93A, directly affect and sensitize sensory neurons to stress.

ABSTRACT

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 (SOD1G93A), directly affect sensory neurons. Here, we examined the effect of mutant TAR DNA-binding protein 1 (TDP43A315T) on sensory neurons in culture and in vivo. In parallel, we reevaluated sensory neurons expressing SOD1G93A. We found that cultured sensory neurons harboring either TDP43A315T or SOD1G93A 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 TDP43A315T elaborate shorter and less complex neurites, and are more sensitive to vincristine compared to controls and to SOD1G93A expressing sensory neurons. Additionally, levels of two molecules involved in stress responses, ATF3 and PERK are significantly different between sensory neurons harboring TDP43A315T to those with SOD1G93A 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.