ATF4 activates a transcriptional program that chronically suppresses mTOR activity promoting neurodegeneration in Parkinson’s disease models

Summary The Integrated Stress Response (ISR) is a cell signaling pathway that enables cells to adapt to diverse cellular stresses. Conversely, during chronic/unmitigated cellular stress the ISR becomes maladaptive and has been implicated in a range of neurodegenerative conditions including Parkinson’s Disease (PD). However, the mechanisms by which maladaptive ISR/ATF4 signaling contributes to neurodegeneration have not been elucidated. In this study we establish a critical mechanism by which chronic ISR activation becomes maladaptive and promotes neurodegeneration in neurotoxin and α- synucleinopathy models of PD in vitro and in vivo . Specifically, we demonstrate that chronic activation of ATF4, the central transcription factor of the ISR, promotes neurodegeneration by regulating the transcriptional induction of SESN2, DDIT4 and Trib3 that co-operate to suppress both mTORC1 and mTORC2 activity. Furthermore, we demonstrate that ATF4-mediated suppression of mTORC1/2 activity promotes dopaminergic neuronal death in PD models by facilitating the activation of the pro- apoptotic BCL-2 family protein PUMA. Taken together, we have discovered a novel maladaptive ISR/ATF4 signaling pathway leading to chronic suppression of mTORC1/2 activity resulting in PUMA-mediated neuronal death that may have therapeutic implications in a range of neurodegenerative conditions that exhibit chronic ISR activation. Abstract Figure