What is schizophrenia?
Schizophrenia is a chronic disorder of the brain of which no cure is known. There are some treatments that are enhancing patient quality of life but there are a number of comorbid conditions lowering life expectancy like diabetes and heart disease. Some of the symptoms that may occur in adolescence are issues with motivation, poor social relationships and problems with attention. Later, these can manifest into disorganized and impaired thinking along with potential hallucinations. Men usually experience onset at about 20 while females are a few years later. Interestingly, each individual case of schizophrenia is different from others. While some may be strong in positive symptoms, hallucinations, these can range from flashing light apparitions to dangerous people following you on the street. On the other hand, negative symptoms can create a catatonic like state in some. How can this huge range of symptoms be caused be the same areas of dysfunction?
How does schizophrenia develop?
There is a development hypothesis of schizophrenia called the “two hit” approach, meaning there are two key points in development when factors can fall into place to lead to schizophrenia. The first is during the end of the first trimester of fetal development as many individuals diagnosed with schizophrenia have low set ears and highly connected toes- areas that form during this time period. The second important “hit” is during adolescence as this is when some of the early symptomology of schizophrenia begins to appear. Not only are there structural differences between those with and without schizophrenia, some issues with cell signaling has become implicated as well, with the Wnt pathway playing a large roll.
How is the Wnt pathway involved?
When the Wnt ligand binds to the receptor complex, parts from a larger destruction complex are recruited to the membrane (APC and Dvl), effectively destroying the structure that held them together. One specific molecule, GSK3, can no longer phosphorylate beta-catenin when the complex is destroyed, keeping b-catenin levels high in the cytoplasm. When beta-catenin level are high, cell stability is increased and the beta-catenin can enter the nucleus and displace Groucho from transcription factors TCF and LEF so that transcription can occur.
Conversely, when WNT does not bind to the receptor, the destruction complex does not break apart, so beta-catenin continues to be phosphorylated by GSK3 and then is targeted for breakdown. When that happens, there is no beta-catenin that enters the nucleus and Groucho remains lodged to TCF and LEF, preventing cell transcription.
Why does all this matter?
Schizophrenia is a debilitating disorder that can include a number of positive and negative from hallucinations to withdraw from society. The Wnt signaling pathway is highly important in the etiology and development of the disorder as it prominent in the neural development and adult neural circuit function. As discussed above, when the Wnt pathway is off, cell transcription of TCF and LEF can’t occur meaning specific genes are not turned on or off. However, we aren’t exactly sure where to intercept this process for treatment completely because our animal models aren’t exact- animals can not get schizophrenia. This disorder is multifaceted and includes many different factors, both structural and signaling wise, making it difficult to know where to begin for new pharmacological therapies.
https://www.psychiatry.org/patients-families/schizophrenia/what-is-schizophrenia
