In a new study, Johns Hopkins Medicine researchers unveiled new evidence showing that some schizophrenia brains are marked by a buildup of abnormal proteins similar to those found in the brains of people with neurodegenerative disorders such as Alzheimer’s or Huntington’s diseases.
The findings, published in the American Journal of Psychiatry, are based on brain tissue samples of deceased human donors (average age 49). The researchers analyzed 42 samples from schizophrenia patients as well as 41 brain samples from healthy controls. Around 75 percent of the brains came from men, and 80 percent were from white subjects.
Based on their experience with schizophrenia and neurodegenerative disorders, the research team wanted to determine if the features of schizophrenia brains could also be seen in the brains of patients with Alzheimer’s disease or other illnesses.
“The brain only has so many ways to handle abnormal proteins,” says Frederick Nucifora Jr., DO, PhD, MHS, the leader of the study and an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.
“With schizophrenia, the end process is mental and behavioral, and doesn’t cause the pronounced physical neural cell death we see with neurodegenerative diseases, but there are clearly some overall biological similarities.”
In neurodegenerative disorders, certain abnormal proteins are churned out but don’t assemble into properly functioning molecules; instead they end up misfolded, clumping up and leading to disease.
For the study, the team broke open the cells from the brain tissue samples and analyzed their contents by looking at how much of the cell’s contents could be dissolved in a specific detergent. The more dissolved contents, the more “normal” or healthy the cell’s contents.
On the other hand, less dissolved cell contents indicated that the cell contains a high volume of abnormal, misfolded proteins, as found in other brain diseases.
The team discovered that slightly less than half (20) of the schizophrenia brains had a greater proportion of proteins that couldn’t be dissolved in detergent, compared to the amount found in the healthy samples.
These same 20 samples also showed elevated levels of a small protein ubiquitin that is a marker for protein aggregation in neurodegenerative disorders. Elevated levels of ubiquitin weren’t seen in the healthy brain tissue samples.
Importantly, the team wanted to confirm that the antipsychotic medications the patients were taking before they died didn’t cause the accumulation of abnormal proteins. To clarify this, they examined the proteins in the brains of rats treated with the antipsychotic drugs haloperidol or risperidone for 4.5 months compared to control rats treated with plain water.
The results reveal that treatment with antipsychotic medications didn’t cause an accumulation of undissolvable proteins or extra ubiquitin tags, suggesting that the disease — and not the medication — caused the abnormal protein build-up in some of the brains with schizophrenia.
Next, the researchers used mass spectroscopy to determine the identity of these undissolvable proteins. They found that many of these abnormal proteins were involved in nervous system development, specifically in generating new neurons and the connections that neurons use to communicate with one another.
Nucifora says the main finding of abnormal proteins in nervous system development is consistent with theories that trace schizophrenia’s origins to brain development and to problems with neural communication.
“Researchers have been so focused on the genetics of schizophrenia that they’ve not paid as much attention to what is going on at the protein level and especially the possibility of protein aggregation,” says Nucifora. “This may be a whole new way to look at the disorder and develop more effective therapies.”
Source: Johns Hopkins Medicine