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ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis

Jorge Gómez-Deza1, Matthew Nebiyou2, Lara H El Touny3

  • 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; Fox Chase Cancer Center, Cancer Signaling and Microenvironment Program, Philadelphia, PA, USA.

Neuron
|May 20, 2026
PubMed

Insights

Activating transcription factor 2 (ATF2) is crucial for neuronal apoptosis in neurodegenerative diseases. Targeting ATF2 prevents cell death, offering a new therapeutic strategy for these disorders.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Neuronal apoptosis is a hallmark of neurodegenerative diseases.
  • The molecular mechanisms driving neuronal cell death are not fully understood.
  • Targeting apoptosis pathways is a key strategy for treating neurodegenerative disorders.

Purpose of the Study:

  • To identify novel genes regulating neuronal apoptosis using a genome-wide screen.
  • To elucidate the molecular mechanisms of neuronal cell death.
  • To evaluate activating transcription factor 2 (ATF2) as a therapeutic target.

Main Methods:

  • Genome-wide CRISPR inhibition screen in human neurons.
  • Mechanistic studies investigating kinase signaling and transcription factor activity.
  • In vitro and in vivo models of neuronal apoptosis.

Main Results:

  • A CRISPR screen identified genes essential for neuronal apoptosis, including dual leucine zipper kinase (DLK), JUN, and ATF2.
  • ATF2 phosphorylation by MAP3 kinases is a critical pro-apoptotic event.
  • Phospho-ATF2 upregulates JUN, mediating the transcriptional response required for cell death.
  • Inhibition of ATF2 function significantly reduced neuronal apoptosis.

Conclusions:

  • ATF2 plays a pivotal role in the pro-death signaling cascade leading to neuronal apoptosis.
  • Targeting ATF2 presents a promising therapeutic avenue for neurodegenerative diseases.
  • This study uncovers a novel molecular mechanism regulating neuronal cell death.
Keywords:
ATF2CRISPRi screenDLKJUNLZKMAP3K12cytoskeletal stressneuron deathneuron injury signalingneuronal apoptosis

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