Related Experiment Video

Updated: Sep 15, 2025

Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
07:42

Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c

Published on: June 29, 2011

17.5K

ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis

Jorge Gómez-Deza1,2, Matthew Nebiyou1, Lara H El Touny3

  • 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Biorxiv : the Preprint Server for Biology
|July 14, 2025
PubMed

Insights

Activating transcription factor 2 (ATF2) drives neuron death in neurodegenerative diseases by converting kinase signals into a transcriptional response. Inhibiting ATF2 protects neurons, offering a new therapeutic target.

Area of Science:

  • Neurobiology
  • Molecular mechanisms of neurodegeneration

Background:

  • Apoptotic neuron death is a hallmark of neurodegenerative diseases.
  • Targeting this pathway is challenging due to incompletely understood molecular mechanisms.

Purpose of the Study:

  • To identify novel genes involved in neuronal apoptosis using a whole-genome CRISPR inhibition screen.
  • To elucidate the role of transcription factor ATF2 in the apoptotic pathway.

Main Methods:

  • Unbiased whole-genome CRISPR inhibition screen in human neurons.
  • Analysis of gene targets, including MAP3K12 (DLK) and JUN.
  • Investigation of ATF2 phosphorylation and its role in transcriptional response.
  • Assessment of ATF2 knockdown effects in neuronal cultures and *in vivo* injury models.

Main Results:

  • CRISPR screen identified known targets (MAP3K12, JUN) and implicated ATF2.
  • ATF2 phosphorylation by MAP3 kinases drives the pro-apoptotic transcriptional response.
  • JUN phosphorylation is not required for apoptosis, but ATF2 phosphorylation and JUN upregulation are crucial.
  • Inhibiting ATF2 prevented cell death in cultured neurons.
  • ATF2 knockdown demonstrated neuroprotective effects in *in vivo* injury models.

Conclusions:

  • ATF2 acts as a critical mediator, converting kinase signals into a pro-apoptotic transcriptional response.
  • ATF2 is a promising therapeutic target for neurodegenerative disorders.

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