Matthew D. Demmings

Neuroscience researcher in Sean Cregan's lab at Western University who showed that chronic ATF4 stress signalling shuts down mTOR and kills dopamine neurons in models of Parkinson's disease

Neuroscience Program, Schulich School of Medicine and Dentistry, and Robarts Research Institute, University of Western Ontario (Sean Cregan lab, papers 2020–2026)

In Parkinson's disease the dopamine-making neurons of the midbrain die. Matthew Demmings' 2026 paper in Cell Reports (DEMMINGS2026), from Sean Cregan's lab at Western University in Canada, traced one route to that death. In cell and animal models of the disease, a long-lasting stress response called the integrated stress response kept the transcription factor ATF4 active. ATF4 turned up three genes, SESN2, DDIT4 and TRIB3, whose proteins together lowered the activity of both mTOR complexes, mTORC1 and mTORC2. That sustained loss of mTOR signalling switched on PUMA, a protein that triggers cell suicide, and the neurons died.

Much of the ageing literature treats lower mTOR activity as good. This study is a reminder that neurons need some mTOR signalling to survive, and that chronic shutdown can be harmful. The results come from cell and animal models, not from patients.

The paper builds on Demmings' earlier first-author study from the same lab, published in Cell Death and Differentiation in 2020, which showed that ATF4 promotes the death of neurons exposed to Parkinson's toxins and to clumps of the protein alpha-synuclein. In 2025 Demmings was also first author of a review on how neurons and glial cells interact from brain development to disease, and a co-author of a review on metabolic networks in the healthy brain.

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