To think, feel, talk and move, neurons send messages through electrical signals in the brain and spinal cord.<\/p>\n
This intricate communication network is built of billions of neurons connected by synapses and managed and modified by glial cells. When neurons die, this communication network is disrupted and since this loss is irreversible, neuron death causes sensory loss, motor impairment and cognitive decline.<\/p>\n
An interdisciplinary team of researchers from the University of Notre Dame is investigating the mechanisms of neuron death caused by chronic compression \u2014 such as the pressure exerted by a brain tumor \u2014 to better understand how to prevent neuron loss.<\/p>\n
Published in the Proceedings of the National Academy of Sciences<\/a>, their study found that chronic compression triggers neuron death by a variety of mechanisms, both directly and indirectly. The research is helping lay the groundwork for identifying therapies to prevent indirect neuron death.<\/p>\n \u201cThe impetus for this project was to figure out those underlying mechanisms. In cancer research, most researchers are focused on the tumor itself, but in the meantime, while the tumor is sitting there and growing, it\u2019s damaging the organ that it\u2019s living in,\u201d said Meenal Datta<\/a>, the Jane Scoelch DeFlorio Collegiate Professor of Aerospace and Mechanical Engineering<\/a> at Notre Dame and co-lead author of the study. \u201cWe fully believe that these growth-induced mechanical forces of the tumor as it expands is part of the reason we see damage in the brain.\u201d<\/p>\n As an engineer who leads the TIME Lab<\/a>, Datta studies the mechanics of tumors and the microenvironment, specifically for glioblastoma, an incurable brain cancer. She had found in prior work that tumors damage the surrounding brain. But to understand the mechanisms by which tumors kill neurons from compression alone, Datta needed a \u201chardcore neuroscientist.\u201d<\/p>\n That neuroscientist is Christopher Patzke<\/a>, the John M. and Mary Jo Boler Assistant Professor in the Department of Biological Sciences<\/a> at Notre Dame and co-lead author of the study. Patzke utilizes induced pluripotent stem cells (iPSCs), which are either obtained from external sources or generated directly in his lab<\/a>. Unlike cells derived from fetal tissue, iPSCs are created by reprogramming a donor’s blood or skin cells \u2014 often collected during a routine medical visit.<\/p>\n These cells function like embryonic stem cells and can be differentiated or changed in the lab into any cell type in the body, including neurons.<\/p>\n For this study, iPSCs were used to create neural cells and develop a model system of neurons and glial cells that behave as a neuronal network would in the brain. Researchers grew the cells and then applied pressure to the system to mimic the chronic compression of a glioblastoma tumor.<\/p>\n After compressing the cells, graduate students Maksym Zarodniuk and Anna Wenninger, from Datta and Patzke\u2019s labs respectively, compared how many neurons and glial cells died versus lived.<\/p>\n \u201cFor the neurons that are still alive, many of them have this programmed self-destruction signaling activated,\u201d Patzke said. \u201cWe wanted to understand which molecular pathway was responsible for this; is there a way to save neurons from going down the drain to this cell death mechanism?\u201d<\/p>\n By sequencing and analyzing all messenger RNA from the living neuronal and glial cells, the researchers found an increase in HIF-1 molecules, signalling for stress adaptive genes to improve cell survival, which leads to inflammation in the brain. The compression also triggered AP-1 gene expression, a type of neuroinflammatory response.<\/p>\n Both neurological reactions are indicators that neuronal damage and death is underway.<\/p>\n An analysis of data from the Ivy Glioblastoma Atlas Project<\/a> shows that glioblastoma patients also reflect these compressive stress patterns and gene expression changes as well as synaptic dysfunction in line with the experiment\u2019s results. The researchers confirmed these results by mimicking force via a live compression system applied to preclinical models of brains.<\/p>\n Overall, the findings may help explain why glioblastoma patients experience cognitive impairments, motor deficits and elevated seizure risk. Additionally, the signaling pathways offer opportunities for researchers to explore as drug targets to reduce neuronal death.<\/p>\n \u201cOur approach to this study was disease agnostic, so our research could potentially extend to other brain pathologies that affect mechanical forces in the brain such as traumatic brain injury,\u201d Datta said. \u201cI\u2019m all in on mechanics. Whatever it is that you\u2019re interested in when it comes to cancer, above your question of interest, mechanics is sitting there and many don\u2019t even know they should be considering it.\u201d<\/p>\n The mechanics of compression and its effect on neuron loss is key for future research.<\/p>\n \u201cUnderstanding why neurons are so vulnerable and die upon compression is critical to prevent excessive sensory loss, motor impairment and cognitive decline,\u201d Patzke said. \u201cThis is how we will help patients.\u201d<\/p>\n The study was funded by the National Institutes of Health and the Harper Cancer Research Institute<\/a> (Harper) at Notre Dame. Additional funding and research support from Notre Dame was provided by the Berthiaume Institute for Precision Health<\/a> (Berthiaume), the Genomics and Bioinformatics Core Facility<\/a>, the Center for Research Computing<\/a>, the Histology Core Facility<\/a> and the Integrated Imaging Facility<\/a>. Both Datta and Patzke are affiliated with Notre Dame\u2019s Boler-Parseghian Center for Rare Diseases<\/a> and the Warren Center for Drug Discovery<\/a>.<\/p>\n Datta is a concurrent faculty member in the Department of Chemical and Biomolecular Engineering and faculty advisor for Notre Dame\u2019s graduate programs in bioengineering<\/a> and materials science and engineering<\/a>. She is affiliated with Harper, the Eck Institute for Global Health<\/a>, Berthiaume, NDnano<\/a> and the Lucy Family Institute for Data & Society<\/a>.<\/p>\n Patzke is a faculty advisor for Notre Dame\u2019s graduate programs in biological sciences<\/a> and integrated biomedical sciences<\/a> as well as affiliated with the Center for Stem Cells and Regenerative Medicine<\/a>.<\/p>\n