A Beautiful Mind tells the story of a mathematician, John Nash, and his journey with schizophrenia. This movie gives a Hollywood look into the devastating effects this mental illness had on John’s life. However, scientifically what does this beautiful mind look like? Researchers are still trying to pin point the cause of schizophrenia, however, they have determined an important signaling pathway in the pathology of this mental illness, the Wnt and GSK3 signaling pathway.
The Wnt and GSK3 signaling pathway plays an important role in schizophrenia. A destruction complex exists in the cytosol (the cell’s fluid), which is composed of b-catenin, GSK3b, Axin, CK1a and APC. This destruction complex is basically like a tower for b-catenin, holding it hostage in and eventually destroying it (deactivating it with a proteasome). In the nucleus, there are transcription factors that are only activated with b-catenin, so when the destruction complex is present, specific genes are not being transcribed and ultimately not being expressed. In order to destroy the destruction complex a signaling molecule called Wnt must bind to a receptor (frizzled) on the cell’s membrane. After Wnt binds, a protein on the inside of the membrane named Disheveled (DVL) is activated. Wnt and ultimately DVL are b-catenin’s knight in shining armor, freeing it from its tower by dissociating the destruction complex, and allowing b-catenin to safely continue its journey to the nucleus. In the nucleus, b-catenin binds to transcription factors TCF and LEF which then activates the transcription of specific genes, such as Cyclin D1.
This story of a damsel in distress (b-catenin) and a knight in shining armor (Wnt) plays an important role in the beautiful mind of schizophrenia. In the brain of someone with this mental illness, D2 receptors (dopamine receptors) inhibit an enzyme called Akt. This enzyme usually inhibits GSKb, thus allowing the destruction of the destruction complex. However, when Akt is inhibited it allows GSKb to build higher walls to the tower enabling the imprisonment/ destruction of b-catenin. Therefore, this pathway’s dysregulation leads to specific genes being suppressed instead of expressed.
One way that this schizophrenia is being treated is by targeting and inhibiting D2 receptors. Therefore, Akt is not inhibited and can do its job of inhibiting GSKb, which allows for b-catenin to travel to the nucleus. Antipsychotic drugs are what is used clinically today to do this. Although this may seem happy ending with the management of schizophrenia, there is a long way to go with regards to an effective and sustainable treatment.
Antipsychotic drugs are the drug of choice when it comes to schizophrenia. However, this all depends on the point of view. For physicians, antipsychotics seems like the handsome prince who is here to save the day and to help combat the symptoms an individual faces. For many patients, these drugs alleviate the positive symptoms of schizophrenia but they come at an ugly cost. Patients may feel like Fiona did when her handsome prince turned out to be Shrek, disappointed. Many antipsychotics come with nasty side effects that can cast a shadow on the positive things the drug is doing.
Now that researchers are starting to uncover the mechanisms and pathways behind schizophrenia, hopefully this will eventually lead to the discovery of a beautiful treatment plan or drug that will end in a happily ever for patients.
For more information of the Wnt and GSK3 signaling pathway in Schizophrenia please visit:
https://www.ncbi.nlm.nih.gov/pubmed/23379509
Feature photo from: https://www.medicalnewstoday.com/articles/318454.php
The Beautiful Mind of Schizophrenia
