The Cross-Border Biotech Blog

Parkinson’s disease, a neurodegenerative disease characterized by motor and cognitive deficits, may be caused by mutations in the Parkin gene. The Parkin gene transcribes the Parkin protein, an enzyme which has been implicated in cellular processes including autophagy, or “cell housekeeping,” and cell survival. Recent work from the Montreal Neurological Institute and McGill University’s Department of Biochemistry published in Science magazine demonstrates the crystal structure of the Parkin protein. The crystal structure of a protein offers an excellent idea of the natural conformation a protein adopts; determining the structure of Parkin protein, surely an immense amount of work, will allow for advanced studies of how the protein normally functions, and will increase understanding of how mutations in the Parkin protein lead to the deficits seen in Parkinson’s disease.

Parkin protein normally has low basal activity. Following determination of the structure of Parkin, the authors found that it can maintain this low baseline by inhibiting itself. Additionally, by testing a number of mutations in the Parkin protein, they found that most mutations greatly reduce or abolish its already low basal activity. However, mutations directed at eliminating auto-inhibition of Parkin were able to increase activity of the protein, indicating that it is possible to bidirectionally change its activity. These experiments demonstrate the utility of knowing the crystal structure of the Parkin protein, as future studies will be able to better evaluate how the activity of the protein can be managed, which may prove very important in the treatment of Parkinson’s disease.

Stroke is the leading cause of disability in North America, but no good treatment exists for stroke beyond a few hours of its occurrence. The damaging effects of stroke occur because nerve cells in the brain require oxygen to survive; once blood-flow to the brain is disrupted and oxygen delivery to nerve cells stops, the cells enter a state called excitotoxicity and begin to die. The best way to improve stroke outcome is to limit the amount of nerve cell death that occurs. Much pharmacological treatment has been directed at inhibiting a specific neurotransmitter receptor central to excitotoxicity, but this approach can have broad effects within the brain. New research from Dr. Yu Tian Wang’s lab at the University of British Columbia published in the Journal of Neuroscience offers a potential new target to limit nerve cell death following stroke. The researchers found that PTEN, a protein that promotes cell death once it enters the nucleus of a cell, becomes targeted to nerve cell nuclei after excitotoxicity starts; additionally, they found that a specific portion of PTEN is critical for its entry in to the nucleus. In nerve cells that were pharmacologically treated to become excitotoxic, ones that had this portion of PTEN mutated were less likely to die. Furthermore, mice injected with a peptide that inhibits the entry of PTEN in to the cell nucleus experienced less extensive physical brain damage, increased nerve cell protection, and more rapid and complete motor skill recovery following an induced stroke; these effects were seen if the peptide was delivered to mice up to 6 hours after the stroke was induced. These results indicate that limiting nerve cell death through inhibition of a downstream protein involved in excitotoxicity may be a viable new approach for stroke treatment, one which may also extend the treatment window following the occurrence of a stroke.

The use of oncolytic viruses is becoming an increasingly attractive avenue for the treatment of cancer, because these viruses are able to destroy tumor cells and also generate immune-responses directed at those same tumor cells. Using human viruses for this type of treatment may be inefficacious, because immunity may exist or quickly develop toward the virus that is being used. The use of animal viruses similar to human viruses may prove to be an effective way to avoid these potential immunity problems.

A proportion of cells within a tumor are cancer stem cells, which are often enriched in what is called a “side population” of tumor cells. These cells can self-renew, produce new cells derived from multiple cell lineages, and may increase the growth rate of tumors. Previous research from Dr. Karen Mossman’s lab at the McMaster University Immunology Research Centre demonstrated that bovine herpesvirus type 1 targets transformed human cells but not normal human cells, and new research from her lab published in Cancer Gene Therapy now demonstrates that this virus can infect and kill cancer stem cells within the tumor side population.

The researchers found that exposing a number of different breast cancer cell lines to the bovine herpesvirus 1 led to a decrease in tumor cell viability and an increase in tumor cell death. The virus also killed human breast cancer stem cells, and limited the self-renewal and cellular differentiation capabilities of these cells. Additionally, mice injected with breast cancer stem cells that had been exposed to bovine herpesvirus 1 formed much smaller tumors than mice that were injected with breast cancer stem cells that were untreated. These results offer hope that bovine herpesvirus 1 or similar viruses may be particularly useful in treating cancers, because, in addition to not targeting normal cells, they are effective in killing the particularly harmful cancer stem cell population, and their use could also limit immunity issues that may reduce treatment efficacy.

Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are autoimmune disorders in which persistent bowel inflammation leads to physical damage of the intestinal tract. Research out of the Inflammation Research Network at the University of Calgary, and published in the Proceedings of the National Academy of Sciences, offers a cool novel target for the treatment of IBD. Just like we have receptors that signal heat, evident when we get a hot or burning sensation when eating a chili pepper, we also have receptors that signal cold, which can be activated by compounds such as menthol. The researchers found that a receptor that signals cold (TRPM8) is expressed more highly in colon samples from humans with Crohn’s disease than in samples from those that do not have IBD. This finding suggests that the TRPM8 receptor is up-regulated in inflamed tissue in an attempt to cool it, similar to how controlled cooling is used to treat sites of traumatic injury.

To investigate the potential of the TRPM8 receptor as a target for inflammation reduction, the researchers performed experiments in mice in which colitis had been induced. Mice with induced colitis expressed the TRPM8 receptor more highly in their colon than mice that did not have induced colitis. The mice with induced colitis also had high levels of cytokines, signalling molecules that can promote inflammation, in their colon; activating the TRPM8 receptor with a molecule called icilin reduced these cytokine levels to normal. Activation of the TRPM8 receptor in mice with induced colitis also decreased the release of a pro-inflammatory neuropeptide in the gut, and, most importantly, limited the amount of physical damage that occurred to the colon. These findings characterize the TRPM8 receptor as an anti-inflammatory receptor, and highlight its potential as a target for therapeutics directed at reducing inflammation in IBD and other chronic inflammatory diseases.

Anxiety disorders are becoming increasingly prevalent in our society, and are highly detrimental to an individual’s well being, both physically and mentally. Children with autism spectrum disorder (ASD) are particularly susceptible to anxiety disorders, but their deficits in communication often make it difficult for them to express feelings of anxiousness. Being unable to express these feelings may lead to an exacerbated anxiety response in children with ASD, because they are often exceedingly aware of their surroundings and may become more socially withdrawn. A study published in PLoS One led by Dr. Azadeh Kushki at the Holland Bloorview Kids Rehabilitation Centre in Toronto sought to address this problem by determining a physiological marker that signals anxiety in children with ASD, which would allow for improvement in their care.

Children with ASD and typically developing children performed an anxiety-inducing task while activity of the autonomic nervous system, the part of our nervous system that unconsciously controls visceral functions, was evaluated using three different measures. The researchers found that two of these measures, heart rate and perspiration, were elevated even at rest in children with ASD, whereas the third measure, skin temperature, was comparable at rest between children with ASD and typically developing children. However, during the anxiety-inducing task the skin temperature of children with ASD increased, whereas the skin temperature of typically developing children decreased, the normal response during stress.

The results of this study offer three important findings. First, the observation that heart rate and perspiration are elevated at rest in children with ASD supports previous reports that these children have elevated generalized anxiety. Second, the difference in changes in skin temperature between children with ASD and typically developing children observed during the stressful task offer a potential non-invasive measure of anxiety in children with ASD. Finally, the generalized difference in visceral functions observed between children with ASD and typically developing children indicates that children with ASD experience inappropriate regulation of their autonomic nervous system, specifically over-activity in the division of the autonomic nervous system that controls stress responses. This final finding warrants further investigation in order to understand whether inappropriate regulation of the autonomic nervous system contributes to increased generalized anxiety in children with ASD, or if it simply accompanies general anxiety caused by other characteristics of the disorder.