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

Demmings MD, Kane EA, Tennyson EC, Hurley K, Zhao J, Cruickshanks NA, Ciz V, Krupa JM, Pasternak SH, Cregan SP · 2026 · Cell Reports · Atlas ID DEMMINGS2026

What this study shows

Chronic integrated-stress-response signalling through ATF4 coordinately upregulates SESN2, DDIT4 and Trib3, which together suppress BOTH mTORC1 and mTORC2; this sustained mTOR inhibition drives dopaminergic neuron death via the pro-apoptotic BCL-2 family protein PUMA. Defines a maladaptive ISR/ATF4-to-mTOR axis in Parkinson disease models — a case where LESS mTOR activity is harmful, opposite to the usual longevity framing.

Abstract

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The integrated stress response (ISR) enables cells to adapt to diverse cellular stresses, but during chronic or unresolved stress it becomes maladaptive and is implicated in neurodegenerative diseases, including Parkinson disease (PD). The mechanisms underlying maladaptive ISR-driven neurodegeneration, however, remain poorly defined. Here, we find a critical pathway by which chronic ISR activation promotes neurodegeneration in neurotoxin and alpha-synucleinopathy models of PD in vitro and in vivo.

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At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mouse (neurotoxin and alpha-synucleinopathy PD models) and cultured neurons) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Mouse (neurotoxin and alpha-synucleinopathy PD models) and cultured neurons
Journal	Cell Reports
Year	2026
Peer reviewed	Yes
Record last updated	2026-08-22
Source	DOI 10.1016/j.celrep.2026.117832 · PMID 42599806

Extracted findings

Target

ATF4 / SESN2 / DDIT4 (REDD1) / TRIB3 / mTORC1 / mTORC2

Cite this paper

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Demmings, M. D., Kane, E. A., Tennyson, E. C., Hurley, K., Zhao, J., Cruickshanks, N. A., Ciz, V., Krupa, J. M., Pasternak, S. H., & Cregan, S. P. (2026). ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models. Cell Reports. https://doi.org/10.1016/j.celrep.2026.117832

@article{DEMMINGS2026,
  author       = {Demmings, M. D. and Kane, E. A. and Tennyson, E. C. and Hurley, K. and Zhao, J. and Cruickshanks, N. A. and Ciz, V. and Krupa, J. M. and Pasternak, S. H. and Cregan, S. P.},
  title        = {{ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models}},
  journal      = {Cell Reports},
  year         = {2026},
  doi          = {10.1016/j.celrep.2026.117832},
  note         = {PMID: 42599806},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record DEMMINGS2026) [Data set]. https://mtor-atlas.org/study/DEMMINGS2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_DEMMINGS2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record DEMMINGS2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/DEMMINGS2026/},
  doi          = {10.5281/zenodo.22059963}
}