Matthew D. Demmings – Robarts Research Institute, University of Western Ontario
Matthew D Demmings, Elizabeth C Tennyson, Gillian N Petroff, Heather E Tarnowski-Garner, Sean P Cregan Activating transcription factor-4 promotes neuronal death induced by Parkinson’s disease neurotoxins and α-synuclein aggregates. Cell Death & Differentiation 28, 1627–1643 (2021) (published Dec 4, 2020). https://www.nature.com/articles/s41418-020-00688-6
Better understanding the molecular mechanisms underlying neuronal death in Parkinson’s disease
Parkinson’s disease is the second most common neurodegenerative disorder, affecting approximately 1 person in 500 in Canada. It results from the loss of a specific class of neurons, called dopaminergic neurons in a brain region called the substantia nigra. It is a chronic, progressive degenerative neurological disease which predominantly affects the older population. Unfortunately, Matt has experienced first-hand the devastating effects of these diseases. After losing his grandfather to Lewy-body dementia in 2019 and watching his grandmother continuously battle advanced Parkinson’s disease he knows much work is needed to better understand the pathophysiology associated with these brain diseases.
While we know that dopaminergic neurons of the brain die in Parkinson’s disease, the mechanisms underlying this neuronal loss remain largely unknown. Research by Matthew Demmings and colleagues now shows that a protein called Activating transcription factor-4 (ATF-4) plays a key role in promoting the death of dopaminergic neurons in PD. This data offers several potential targets for the development of novel therapeutic strategies for the treatment of Parkinson’s disease.
Prior to this study, increased levels of ATF4 had been reported in cellular and animal models of PD as well as in brain tissue of PD patients obtained after death. Despite these findings, the role of ATF4 in regulating neuronal survival remained controversial. In this study, Demmings and colleagues have demonstrated an important role for ATF-4: ATF-4 induction in cellular models of PD promotes dopaminergic neuron death through activation of known pro-death genes. Moreover, this study provided mechanistic insights into the processes by which dopaminergic neurons die in response to oxidative stress and alpha-synuclein aggregation. Furthermore, this study provides evidence for the protective effect of pharmacologically downregulating ATF-4 using a small molecule called C16. This work provides foundational knowledge for future investigation of ATF-4 in animal models of PD. Ultimately, this research could lead to the development of novel therapeutic strategies for the treatment of Parkinson’s disease.
Matthew D. Demmings
As first author, Matt Demmings conceptualized and designed all experiments in consultation with Sean Cregan. He executed the vast majority of all scientific experimentation, was also responsible for the statistical analysis of data sets and wrote the majority of the manuscript under the supervision of Sean Cregan. This work was funded by grants from CIHR and Heart and Stroke Foundation. In addition, Matt’s training has been generously supported by Ontario Graduate Scholarships, awards from Schulich School of Medicine and Dentistry, and further support from the International Society for Neurochemistry and the Society for Neuroscience.