Battle for the Brain: Experimental Cancer Drug vs. Schizophrenia

Cancer… it is one of the most devastating and debilitating diseases to have ever affected the human race. It annually results in millions of deaths worldwide, and costs billions upon billions of dollars to provide treatment and to fund research for a cure. There have been many chemotheraputic drugs developed that have taken major strides towards reducing the effects of uncontrolled cell growth and tumor formation; however, a substantial portion of these drugs have also been found to have alternative effects, which include reversing the actions of other diseases. Here is where the fight to eradicate schizophrenia comes into play. This brand new research, that is about to be described, could possibly be the first major step towards eliminating this psychological disorder once and for all. Earlier in our journey into unlocking the secrets of this debilitating mental condition, we focused on possible biochemical and genetic causes of the disease. Now we will delve right into a some fresh and exciting new research in order to get a taste of the process that can potentially lead to future treatments.

Recently, a group of researchers working at the John Hopkins School of Medicine have found that an experimental cancer compound has apparently reversed behaviors associated with schizophrenia and has also restored lost brain cell function in mice that have a rodent version of the disease. The drug in question is known as a p21-Activated Kinase (PAK) inhibitor, which serves to inhibit the actions of PAK proteins. PAK proteins are implicated in a wide range of biological functions involving cellar motility and morphology, but they have been also shown to promote erratic cell growth. Previous studies involving PAK inhibitors have shown that they have been able to provide animal models a degree of protection from brain damage due to Fragile X syndrome, which is a genetic syndrome that leads to mental retardation in humans. There is also evidence that these inhibitors could be used to treat Alzheimer’s disease as well. The fact that this PAK inhibitor has shown promise in combating other neurological conditions, leaves no reason to doubt its effectiveness in fighting schizophrenia.

The John Hopkins team led by Dr. Akria Sawa discovered that the PAK inhibitor compound, known as FRAX486, showed signs of halting the aberrant “pruning” phenomenon that occurs within a schizophrenic brain (Figure 1). This pruning process involves the unnecessary destruction of significant neural connections, in a uncontrollable manner. Within the mouse test subjects, with neurological conditions that mimicked schizophrenia, the researchers were also able to moderately restore normal function to disabled neurons, which allowed them to reform connections with other nerve cells. Blocking the effects of unruly pruning, while revitalizing brain function should effectively reduce any behavior deficits, which has fascinating implications for combating the disorder. Since schizophrenia is known to typically rear its ugly head in late adolescence and early adulthood, the researchers focused on this stage of development with the mice. The promising results with the PAK inhibitor in teenage mice may lead to the development of superior treatments that can be applied to humans in the future.

frax486Figure 1: Molecular structure of the PAK inhibitor FRAX486

Now that we have been introduced to this potential schizophrenia “miracle drug” let’s take a closer look at the actual science behind the John Hopkins team’s research. Firstly, for these experiments involving mice, the expression of the Disrupted-in-Schizophrenia (DISC1) gene was reduced, in order to mimic the conditions in a human schizophrenic brain. This DISC1 gene codes for a protein that seems to act as a regulator for nerve cell fate within the cerebral cortex, which is the part of the brain that deals with higher levels of function, such as memory, attention, language and consciousness. The researchers found that a DISC1 deficit led to the degradation of essential parts of the neuron, known as spines, which helps with neuronal communication (Figure 2). Also a reduction in the DISC1 protein affects the development of the Kalirin-7 (KAL7) protein, which regulates another protein called Rac1. Rac1 plays a role in neuronal spine development, and KAL7 cannot sufficiently control Rac1 production when there is a lack of the DISC1 protein. This lead to an excessive amount of Rac1 being produced, resulting in the elimination of the spines and also excess PAK production, leading to nerve cell damage in the mice.

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Figure 2: Dendritic spines shown on a nerve cell

In order to protect the spines from being degraded due to a lack of DISC1, the research team introduced the FRAX486 PAK inhibitor in small doses to reduce PAK activity. This halted the excess pruning that was observed and lead to the restoration of spines within the mice brains. Also the drug did not seem to lead to any adverse effects and appeared to be safe for use in animals. However it must be noted that an increase in PAK has not yet been shown to occur within human schizophrenic brains. Therefore it must be determined if there is a wild PAK activity within humans before any potential treatments can be developed.

Another interesting observation was that the mice introduced to the PAK inhibitor exhibited improved behavior, compared to the schizophrenic ones. They were tested for their reactions to startling sounds, where they were primed to hearing a weaker one before being introduced to a startling one. The schizophrenic mice had no distinct reaction to the sounds, whereas the treated mice showed more typical reactions.

This riveting study has uncovered a promising possible treatment for those suffering from this complex psychological condition. This drug has been shown to have the potential to reverse neurological damage related to schizophrenia, while also preventing any further damage. It may be a glimmer of hope for those haunted by those ominous voices, as it was also shown to ultimately improve the behavior of those affected. As I have mentioned before, there is no simple way to cure this disease, but every discovery made takes us one step closer to finding one. I hope that this has been a highly informative and rewarding journey into understanding the secrets of this fascinating disease, and hopefully the exciting discoveries we have learned about will one day play a part in eradicating it forever…

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Johns Hopkins Medicine. “Experimental cancer drug reverses schizophrenia in adolescent mice.” ScienceDaily. ScienceDaily, 31 March 2014. .

Dolan, B. M., S. G. Duron, D. A. Campbell, B. Vollrath, B. S. S. Rao, H.-Y. Ko, G. G. Lin, A. Govindarajan, S.-Y. Choi, and S. Tonegawa. “Rescue of Fragile X Syndrome Phenotypes in Fmr1 KO Mice by the Small-molecule PAK Inhibitor FRAX486.” Proceedings of the National Academy of Sciences 110.14 (2013): 5671-676.

Unlocking the Secrets of Schizophrenia…

Imagine you lived in a world where you are constantly harassed by ominous voices that materialize out of thin air, or are being persecuted by strange and dangerous forces. This might sound like something out of terrifying horror movie to you, but in actuality there exists a number of people that experience this distorted view of reality. These people have a devastating psychological condition known as schizophrenia. This debilitating mental illness affects approximately 1% of the world’s population and can lead to significant social and emotional problems. Some of the symptoms include perplexing delusions and hallucinations, disorganized behavior and speech, a lack of motivation and emotion, as well as the feeling that someone is out to get you. Although this disorder affects a large number of people not much is known about the causative factors that lead to its appearance in affected individuals. However, most researchers and clinicians believe that it results from a combination of genetics, environmental factors, and various other social and psychological influences. To begin our journey into understanding the roots of the disease from a biochemical perspective, we will delve into some recent research in order to elude as much as we can about its causation.

394278_10150578499573688_1106047655_nA representation of possible visual hallucinations that schizophrenia patients might experience…

Two recent scientific studies have yielded interesting results in regards to factors that lead to schizophrenia. One of them deals with observing whether an interaction between genes and a common virus, known as cytomegalovirus, increases the risk of developing schizophrenia. The second study examines jumping DNA in the brain, called retrotransposons, which may also be implicated in causing the disorder. There are many possible biochemical influences that are involved with the causation of schizophrenia, but these two fascinating examples may be able to help us scratch the surface in regards to understanding this baffling condition.

Let’s first take a look at the cytomegalovirus, and see how its interactions within the brain can open a door for schizophrenia to rear its ugly head. The cytomegalovirus (abbreviated as CMV) is part of the Herpesviridae viral family, which are known to be extremely widespread among humans. Herpesviridae viruses can remain dormant within cells for extended periods of time, and approximately 90% of adults have been infected within their lifetime. CMV can be found throughout the body; however, it is commonly correlated with salivary gland infections. CMV rarely shows symptoms in healthy individuals, but it can be a cause for alarm in pregnant women or people with a weakened immune system. In these cases symptoms include pneumonia, diarrhea, and ulcers in the digestive tract. Furthermore, infected pregnant women can pass the virus on to their unborn baby, which is one reason why researchers looking at schizophrenia’s causative factors are interested in examining CMV.

Several studies have found an association between CMV and schizophrenia; therefore, a research team at Aarhus University in Denmark decided to examine whether maternal CMV infection had any relations to schizophrenia. A genome-wide association study was conducted, which scanned the entire genome of  882 healthy individuals and 888 affected  Danish people, to see if CMV integration into the genome had effects on genes related to schizophrenia development. As it turns out that is exactly what they seemed to have uncovered. As was mentioned before, schizophrenia seems to develop once certain environmental stresses affect individuals that have distinct genetic risk factors.  Also, previous studies have shown that maternal infection is one of these risk factors that may lead to an increased risk of a child developing schizophrenia at a later point in their life. In this case it was found that women infected with CMV have an increased risk, which is 5 times higher than normal, of giving birth to a child that will become affected by schizophrenia. This risk is attributed to children who inherit the specific gene variant that interacts with the virus from the mother. Although this relation was found, the researchers stressed that it is no cause for alarm; as there may be several other factors that prevent the disease in the child, even if both risk factors are found in the mother and child.

Taking a more specific look at the science behind the CMV research, the genome wide association study that was conducted examined  the  association of single-nucleotide polymorphisms (SNPs) with the prevalence of schizophrenia in affected persons. SNPs are DNA sequence variations occurring when a single nucleotide in the genome differs between  members of a species. The interaction discovered in the study was between the gene CTNNA3, which has been shown to be involved with cell to cell connections in the brain. and maternal CMV infection. Although the discovery of this interaction may not be an earth-shattering revelation, it still shows how something as obscure as a mild viral infection can lead to the debilitating schizophrenic experiences.

Now let’s take a look at the bizarre “jumping DNA” sequences that are present in the brain, how they have an effect on schizophrenia. Retrotransposons  are a class of jumping DNA, which exist as short fragments of DNA that autonomously replicate via an RNA intermediate and move around the genome, sometimes reinserting themselves within genes, causing a disruption to their functions. Long Interspersed Nuclear Elements (LINE) are a type of retrotransposon that make up a large portion of the eukaryotic genome, and are believed to be implicated in a number of diseases, including cancer. LINE-1 retrotransposons have been shown to abundant brain cells, compared to cells in the rest of the body, which show that they are more active in the brain. Interestingly,  researchers from the University of Tokyo discovered a correlation between LINE-1 expression and schizophrenia.An increased number of LINE-1 copies was found in post-mortem brains of individuals with schizophrenia, as well as in mice that were used as neurodevelopmental models for schizophrenia. Increased LINE-1 was specifically observed in prefrontal cortex neurons, which is implicated in moderating social behavior. In regards to the mouse models, an increased number of LINE-1 retrotransposons were also observed after introducing external stress in the form of epidermal growth factor. This suggests that the combination of environmental triggers, as well as LINE-1 hyperactivity in the brain, may contribute to schizophrenia development. These observations give some insight into how a certain biological factor may be lead to schizophrenia in a specific way. The disruption of functional genes in the prefrontal cortex by these jumping DNA sequences is a startling development, because anomalies in this region of the brain (such as reduced interconnection between neurons) have been implicated in a large range of mental disorders, including schizophrenia.

transA simple mechanism for the insertion of “Jumping DNA” into a region of the genome

It has been an interesting and informative journey so far, as we have be able to make some inferences on how this mysterious disease manifests itself within individuals. We have learned that obscure elements such as a common virus, and jumping DNA may lead to  this disease, when combined with external environmental stresses. Hopefully additional studies will delve further into finding out the cause, by possibly looking into other related mutations within the genome, or by examining whether there are factors, such as increased retrotransposon activity, that are shared with other mental disorders. Schizophrenia is a complex psychological condition, therefore there exists no simple “fix” for those suffering from the disease. However every discovery made gives us another piece to the puzzle, and one day we may be able to full unlock a cure that will vanquish those ominous voices once and for all…

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A D Borglum, D Demontis, J Grove, J Pallesen, M V Hollegaard, C B Pedersen, A Hedemand, M Mattheisen, A Uitterlinden, M Nyegaard, T Ørntoft, C Wiuf, M Didriksen, M Nordentoft, M M Nöthen, M Rietschel, R A Ophoff, S Cichon, R H Yolken, D M Hougaard, P B Mortensen, O Mors. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci. Molecular Psychiatry, 2013;DOI:10.1038/mp.2013.2

Miki Bundo, Manabu Toyoshima, Yohei Okada, Wado Akamatsu, Junko Ueda, Taeko Nemoto-Miyauchi, Fumiko Sunaga, Michihiro Toritsuka, Daisuke Ikawa, Akiyoshi Kakita, Motoichiro Kato, Kiyoto Kasai, Toshifumi Kishimoto, Hiroyuki Nawa, Hideyuki Okano, Takeo Yoshikawa, Tadafumi Kato, Kazuya Iwamoto.Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia.Neuron, 2014; DOI: 10.1016/j.neuron.2013.10.053