eIF2α phosphorylation evokes dystonia-like movements with D2-receptor and cholinergic origin and abnormal neuronal connectivity

Dystonia is the 3rd most common movement disorder. Dystonia is acquired through either injury or genetic mutations, with poorly understood molecular and cellular mechanisms. Eukaryotic initiation factor alpha (eIF2) controls cell state including neuronal plasticity via protein translation control and expression of ATF4. Dysregulated eIF2 phosphorylation (eIF2-P) occurs in dystonia patients and models including DYT1, but the consequences are unknown. We increased/decreased eIF2-P and tested motor control and neuronal properties in a Drosophila model. Bidirectionally altering eIF2-P produced dystonia-like abnormal posturing and dyskinetic movements in flies. These movements were also observed with expression of the DYT1 risk allele. We identified cholinergic and D2-receptor neuroanatomical origins of these dyskinetic movements caused by genetic manipulations to dystonia molecular candidates eIF2-P, ATF4, or DYT1, with evidence for decreased cholinergic release. In vivo, increased and decreased eIF2-P increase synaptic connectivity at the NMJ with increased terminal size and bouton synaptic release sites. Long-term treatment of elevated eIF2-P with ISRIB restored adult longevity, but not performance in a motor assay. Disrupted eIF2-P signaling may alter neuronal connectivity, change synaptic release, and drive motor circuit changes in dystonia.