There is a lack of reliable treatment options for autism, due in part to a poor understanding of how the disease works on a molecular level. One known cause of autism is fragile X syndrome, which is understood to be caused by a problem with the FMR1 gene. While Fragile X is easy to diagnose, there is no therapy for the disorder. Investigators at Michigan State University (MSU) have made progress in the fight against this disease, discovering a protein that likely plays a critical role in the disorder. Their findings were reported in Nature Communications and are summarized in the following video, and they could eventually be a big benefit to people waiting for treatment.
Fragile X can be traced back to the silencing of the FMR1 gene, but in normal cells, the protein produced by that gene interacts with hundreds of targets, messenger RNA (mRNA) molecules, and it can help regulate the levels of those mRNAs. For this work, the researchers have manages to zero in on one critically important target. They have linked that target to many of the physiological and molecular manifestations of Fragile X.
“We began with 600-800 potential protein targets, searching for the equivalent of a needle in a haystack,” explained one author of the report, Hongbing Wang, MSU physiologist. “Our needle turned out to be ADCY1. When we compared levels of this protein in Fragile X mouse model to normal controls, we saw a 20-25 percent increase of ADCY1.”
To follow up on their findings, the researchers tested the impact of reducing levels of ADCY1; they found that autism-related behaviors were also reduced. Next, they observed that an increase in the level of ADCY1 protein resulted in an increase in neuronal signaling. When those levels were then reduced, the neuronal signaling also went down to a normal level.
In neurons that are affected by Fragile X, they have an excess of features called dendritic spines. Those bumps are especially numerous in the Fragile X neurons but when the researchers reduced levels of the ADCY1 protein, the bumpy appearance of the affected neurons was improved.
This work could eventually be a benefit to patients. Finding a single culprit that’s likely causing so many of the symptoms makes the new data appealing to pharmaceutical companies, Wang said. “Our research has identified a key target and a new approach that could easily be pursued by pharmaceutical companies,” Wang continued.
Already an experimental drug called NB001, which is a possible treatment for pain that passes the blood brain barrier, has shown some positive initial results. “We’ve shown an accessible target that, through treatment using NB001, suppresses activity. The next steps would be to test toxicity and optimization," said Wang.
Wang cautioned that these findings are still a long way from actually being used to treat patients. Future research should not only focus on drug targets; researchers could delve deeper into how these mechanisms are working in younger organisms since this work used an adult mouse model. It would also be important to know if an intervention could be used to help stem the developmental disorders that build throughout a child's life.
Learn more about Fragile X from the video from the CDC.