| First Author | G??mez-Deza J | Year | 2026 |
| Journal | Neuron | Volume | 114 |
| Issue | 12 | Pages | 2183-2198.e10 |
| PubMed ID | 42161275 | Mgi Jnum | J:386317 |
| Mgi Id | MGI:8346753 | Doi | 10.1016/j.neuron.2026.04.035 |
| Citation | Gomez-Deza J, et al. (2026) ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis. Neuron |
| abstractText | Neuronal apoptosis is a key feature of neurodegenerative diseases. Considerable efforts have been made to target this pathway; however, the underlying molecular mechanisms remain incompletely understood. Here, we conducted an unbiased, genome-wide CRISPR inhibition screen in human neurons to discover genes required for cell death. We uncover a multitude of targets required for neuronal apoptosis, some known and many previously unidentified. Among them, three stood out as members of a pro-death cascade: dual leucine zipper kinase (DLK or MAP3K12) and the transcription factors JUN and the lesser-known activating transcription factor 2 (ATF2). Through mechanistic studies, we demonstrate that ATF2 phosphorylation by MAP3 kinases is a critical step in neuronal apoptosis. Surprisingly, JUN phosphorylation is not required. Conversion of the MAP3 kinase signal into a pro-apoptotic transcriptional response requires phospho-ATF2 to upregulate JUN. We show that interfering with ATF2 function prevents neuronal apoptosis in vitro and in vivo. Our work posits ATF2 as a promising target for a wide range of neurodegenerative disorders. |
