Researchers at the University of Miami Miller School of Medicine have discovered that a gene belonging to a gene family known to be involved in cell death in ischemic stroke will, when knocked out (genetically modified), confer protection on neurons, keeping them alive despite the presence of an ischemic insult. This opens the door to possible new treatments for stroke.
An article describing their findings, “Knock-out of a mitochondrial sirtuin protects neurons from degeneration in Caenorhabditis elegans,” was recently published online by the journal PLOS Genetics. Laura Bianchi, Ph.D., associate professor of physiology and biophysics, was corresponding author.
“Stroke is a major public health concern,” said Bianchi. “Resveratrol, an antioxidant present in red wine, has been shown to protect against cardiovascular disease by activation of a family of proteins called sirtuins. Recent studies, however, have shown that the action of sirtuins is complex and, in some cases, can be deleterious. Using the model organism C. elegans, a small soil nematode that shares basic biology processes with mammals, we discovered that a certain sirtuin gene is deleterious in conditions that mimic ischemic stroke.”
In the journal article, the researchers report finding that a knock-out version of this C. elegans sirtuin spares neurons, and that this protective effect is enhanced by placing animals in dietary deprivation or by blocking their glycolysis. They also report that ROS — oxygen-containing chemical species that cause damage in times of stress — are eliminated more efficiently in the sirtuin knock-out than in the wild type. The investigators concluded that inhibition of the mammalian sirtuin, homologous to the worm gene the Bianchi lab studied, combined with dietary deprivation must be explored as a novel therapeutic approach to preventing ischemic damage.
“Experiments are now under way to identify the molecular mechanism underlying the effect of this sirtuin on ischemic damage,” said Bianchi. “Data reported in our article support that the insulin/IGF pathway is involved in the mechanism of protection mediated by the knock-out of this sirtuin gene, but the exact genes involved are still unknown. Nonetheless, the ease of genetic approaches in C. elegans will make identification of these genes straightforward. They can then be tested in mammalian systems for the identification of additional drug targets for the treatment of stroke.”
Other Miller School authors of the study were David Della-Morte, M.D., Ph.D., research associate professor of neurology; Rachele Sangaletti, Ph.D. (first author), and Jeff Grant, Ph.D., both postdoctoral associates in the
Department of Physiology and Biophysics; and Massimo D’Amico, an exchange graduate student from the University of Bologna.
This work was supported by National Institutes of Health Grant RO1NS070969-01A and University of Miami Scientific Awards Committee (SAC) 2014-3R2 pilot grant, both to Bianchi.
Miller School of Medicine