Most likely culprit for schizophrenia

Schizophrenia is eight different diseases

Schizophrenia is eight different diseases

Researchers have found a gene that links the three previously unrelated biological changes most commonly blamed for causing schizophrenia, making it one of the most promising culprits for the disease so far, and a good target for future treatments.

Schizophrenia is a debilitating mental disorder that usually appears in late adolescence, and changes the way people think, act and perceive reality. For decades, scientists have struggled to work out what causes the hallucinations and strange behaviour associated with the disorder, and keep coming back to three neuronal changes that seem to be to blame. The only problem is that the changes seemed to be unrelated, and, in some cases, even contradictory.

But now, researchers from Duke University in the US have managed to find a link between these three hypotheses, and have shown that all three changes can be brought about by a malfunction in the same gene.

Publishing in Nature Neuroscience, the researchers explain that their results could lead to new treatment strategies that target the underlying cause of the disease, rather than the visible changes or phenotypes, associated with schizophrenia.

“The most exciting part was when all the pieces of the puzzle fell together,” lead researcher, Scott Soderling, a professor of cell biology and neurobiology from Duke University, said in a press release. “When [co-researcher Il Hwan Kim] and I finally realised that these three outwardly unrelated phenotypes … were actually functionally interrelated with each other, that was really surprising and also very exciting for us.”

So what are these three phenotypes? The first is spine pruning, which means that the neurons of people with schizophrenia have fewer spines – the long part of a brain cell that passes signals back and forth. Some people with schizophrenia also have hyperactive neurons, and excess dopamine production.

But these changes just didn’t seem to make sense together. After all, how could neurons be overactive if they didn’t have enough dendritic spines to pass messages back and forth, and why would either of these symptoms trigger excess dopamine production? Now, researchers believe that a mutation in the gene Arp2/3 may be to blame.

Soderling and his team originally spotted the gene during previous studies, which identified thousands of genes linked to schizophrenia. But Arp2/3 was of particular interest, as it controls the formation of synapses, or links, between neurons.

To test its effect, the researchers engineered mice that didn’t have the Arp2/3 gene and, surprisingly, found that they behaved very similarly to humans with schizophrenia. The mice also got worse with age and improved slightly with antipsychotic medications, both traits of human schizophrenia.

But most fascinating was the fact that the mice also had all three of the unrelated brain changes – fewer dendritic spines, overactive neurons and excess dopamine production.

They also took things one step further and showed, for the first time, that this lack of dendritic spines can actually trigger hyperactive neurons. This is because the mice’s brain cells rewire themselves to bypass these spines, effectively skipping the ‘filter’ that usually keeps their activity in check.

They also showed that these overactive neurons at the front of the brain were then stimulating other neurons to dump out dopamine.

“Overall, the combined results reveal how three separate pathologies, at the tiniest molecular level, can converge and fuel a psychiatric disorder,” Susan Scutti explains over at Medical Daily.

The group will now study the role Arp2/3 plays in different parts of the brain, and how its linked to other schizophrenia symptoms. The research is still in its very early stages, and obviously has only been demonstrated in mice and not humans. But it’s a promising first step towards understanding this mysterious disease.

“We’re very excited about using this type of approach, where we can genetically rescue Arp2/3 function in different brain regions and normalise behaviours,” Soderling said. “We’d like to use that as a basis for mapping out the neural circuitry and defects that also drive these other behaviours.”

Source:  sciencealert.com

Schizophrenia is eight different diseases

Schizophrenia is eight different diseases

Schizophrenia is eight different diseases

 

New research shows that schizophrenia is not a single disease, but a group of eight distinct disorders, each caused by changes in clusters of genes that lead to different sets of symptoms.

The finding sets the stage for scientists to develop better ways to diagnose and treat schizophrenia, a mental illness that can be devastating when not adequately managed, says C. Robert Cloninger, co-author of the study published Monday in the American Journal of Psychiatry.

“We are really opening a new era of psychiatric diagnosis,” says Cloninger, professor of psychiatry and genetics at the Washington University School of Medicine in St. Louis. Cloninger says he hopes his work will “allow for the development of a personalized diagnosis, opening the door to treating the cause, rather than just the symptoms, of schizophrenia.”

Clonginger and colleagues found that certain genetic profiles matched particular symptoms. While people with one genetic cluster have odd and disorganized speech – what is sometimes called “word salad” – people with another genetic profile hear voices, according to the study, funded by the National Institutes of Health.

Some genetic clusters gave people higher risks of the disease than others, according to the study, which compared the DNA of 4,200 people with schizophrenia to that of 3,800 healthy people.

One set of genetic changes, for example, confers a 95% chance of developing schizophrenia. In the new study, researchers describe a woman with this genetic profile who developed signs of the disorder by age 5, when she taped over the mouths of her dolls to make them stop whispering to her and calling her name. Another patient – whose genetic profile gave her a 71% risk of schizophrenia – experienced a more typical disease course and began hearing voices at age 17.

The average person has less than a 1% risk of developing schizophrenia, Cloninger says.

Psychiatrists such as Stephen Marder describe the the study as a step forward. Today, doctors diagnose patients with mental illness with a process akin to a survey, asking about the person’s family history and symptoms, says Marder, a professor at the David Geffen School of Medicine at the University of California-Los Angeles.

“It underlines that the way we diagnose schizophrenia is relatively primitive,” Marder says.

Patients may wait years for an accurate diagnosis, and even longer to find treatments that help them without causing intolerable side effects.

Doctors have long known that schizophrenia can run in families, says Robert Freedman, editor in chief of the American Journal of Psychiatry and chair of psychiatry at the University of Colorado Anschutz Medical Campus. If one identical twin has schizophrenia, for example, there is an 80% chance that the other twin has the disease, as well.

In the past, doctors looked for single genes that might cause schizophrenia, without real success, Freedman says.

The new paper suggests that genes work together like a winning or losing combination of cards in poker, Freedman says. “This shows us that there are some very bad hands out there,” Freedman says.

 In some cases – in which a genetic profile conveys close to a 100% risk of schizophrenia – people may not be able to escape the disease, Cloninger says. But if doctors could predict who is at high risk, they might also be able to tailor an early intervention to help a patient better manage their condition, such as by managing stress.

Doctors don’t yet know why one person with a 70% risk of schizophrenia develops the disease and others don’t, Clonginger says. It’s possible that environment plays a key role, so that child with a supportive family and good nutrition might escape the diagnosis, while someone who experiences great trauma or deprivation might become very ill.

The study also reflects how much has changed in the way that scientists think about the genetic causes of common diseases, Marder says. He notes that diseases caused by a single gene – such as sickle-cell anemia and cystic fibrosis – affect very few people. Most common diseases, such as cancer, are caused by combinations of genes. Even something as apparently simple as height is caused by combinations of genes, he says.

Doctors have known for years that breast cancer is not one disease, for example, but at least half a dozen diseases driven by different genes, says study co-author Igor Zwir, research associate in psychiatry at Washington University. Doctors today have tests to predict a woman’s risk of some types of breast cancer, and other tests that help them select the most effective drugs.

Those sorts of tests could be extremely helpful for people with schizophrenia, who often try two or three drugs before finding one that’s effective, Cloninger says.

“Most treatment today is trial and error,” Cloninger says.

If doctors could pinpoint which drugs could be the most effective, they might be able to use lower doses, producing fewer of the bothersome side effects that lead many patients to stop taking their medication, Cloninger says.

 

Source:  usatoday.com