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Updated: Aug 16, 2026

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
08:09

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Published on: January 7, 2014

ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in

Matthew D Demmings1, Erica A Kane2, Elizabeth C Tennyson1

  • 1Neuroscience Program, University of Western Ontario, London, ON, Canada; Robarts Research Institute, University of Western Ontario, London, ON, Canada.

Cell Reports
|August 14, 2026
PubMed

Insights

Chronic activation of the integrated stress response (ISR) pathway drives neurodegeneration in Parkinson disease models. This maladaptive ISR/ATF4-mTOR signaling leads to dopaminergic neuron death, offering therapeutic targets for neurodegenerative disorders.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Cellular Stress Response

Background:

  • The integrated stress response (ISR) is crucial for cellular adaptation to stress.
  • Maladaptive ISR activation is linked to neurodegenerative diseases like Parkinson disease (PD).
  • Mechanisms of ISR-driven neurodegeneration remain unclear.

Purpose of the Study:

  • To elucidate the pathway linking chronic ISR activation to neurodegeneration in PD.
  • To identify key molecular players in maladaptive ISR signaling.

Main Methods:

  • Utilized in vitro and in vivo models of PD, including neurotoxin and alpha-synucleinopathy models.
  • Investigated the role of the transcription factor ATF4 and its downstream targets.
  • Assessed the impact on mTORC1/mTORC2 signaling and apoptosis.

Main Results:

  • Chronic ISR activation, mediated by ATF4, upregulates SESN2, DDIT4, and Trib3.
  • These factors cooperatively inhibit mTORC1 and mTORC2 activity.
  • ATF4-dependent mTOR inhibition promotes dopaminergic neuron death via PUMA activation.

Conclusions:

  • A critical maladaptive ISR/ATF4-mTOR pathway promotes neurodegeneration in PD models.
  • This pathway involves ATF4-induced suppression of mTOR signaling, leading to apoptosis.
  • The identified pathway presents a potential therapeutic target for neurodegenerative diseases with chronic ISR activation.
Keywords:
ATF4CP: molecular biologyCP: neuroscienceISRPUMAdopaminergic neuronsintegrated stress responsemTORneurodegenerationα-synuclein

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