Motor neuron activity induces proteomic stress in the target muscle

Abstract

AbstractSeveral lines of evidence demonstrate that increased neuronal excitability can enhance proteomic stress. For example, epilepsy can enhance the proteomic stress caused by the expression of certain aggregation-prone proteins implicated in neurodegeneration. However, unanswered questions remain concerning the mechanisms by which increased neuronal excitability accomplishes this enhancement. Here we test whether increasing neuronal excitability at a particular identified glutamatergic synapse, the Drosophila larval neuromuscular junction, can enhance the proteomic stress caused by mutations in the ER fusion geneatlastin(atl). It was previously shown that larval muscle from theatl2null mutant is defective in autophagy and accumulates protein aggregates containing ubiquitin (poly-UB aggregates). To determine if increased neuronal excitability might enhance the increased proteomic stress caused byatl2, we activated theTrpA1-encoded excitability channel within neurons. We found that TrpA1 activation had no effect on poly-UB aggregate accumulation in wildtype muscle, but significantly increased poly-UB aggregate number inatl2muscle. Previous work has shown thatatlloss from either neuron or muscle increases muscle poly-UB aggregate number. We found that neuronal TrpA1 activation enhanced poly-UB aggregate number whenatlwas removed from muscle, but not from neuron. Neuronal TrpA1 activation enhanced other phenotypes conferred by muscleatlloss, such as decreased pupal size and decreased viability. Taken together, these results indicate that the proteomic stress caused by muscleatlloss is enhanced by increasing neuronal excitability.