ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models.

The integrated stress response (ISR) enables cells to adapt to diverse cellular stresses, but during chronic or unresolved stress it becomes maladaptive and is implicated in neurodegenerative diseases, including Parkinson disease (PD). The mechanisms underlying maladaptive ISR-driven neurodegeneration, however, remain poorly defined. Here, we find a critical pathway by which chronic ISR activation promotes neurodegeneration in neurotoxin and α synucleinopathy models of PD in vitro and in vivo. We show that sustained activation of ATF4, the central ISR transcription factor, induces the coordinated transcriptional upregulation of SESN2, DDIT4, and Trib3, which cooperate to suppress both mTORC1 and mTORC2 activity. This ATF4-dependent inhibition of mTOR signaling promotes dopaminergic neuron death by facilitating activation of the pro apoptotic BCL 2 family protein PUMA. Together, these findings define a maladaptive ISR/ATF4-mTOR pathway with potential therapeutic relevance for neurodegenerative disorders characterized by chronic ISR activation.