Scientists have used an organoid model to gain new insights into Huntington's disease, a fatal genetic disorder that causes neurodenegeration that impairs movement and behavior. The disease is caused by mutations in the Huntingtin (HTT) gene. There are no good treatments for this disorder. Investigators have now found that a gene called CHCHD2 is also related to Huntington's; mutations in the HTT gene can reduce CHCD2 expression, which may present a new target option for treatments. The findings have been reported in Nature Communications.
Researchers turn to models when they want to learn more about the mechanisms underlying a physiological process or disease. But animals can only tell us so much about human conditions. One relatively recent creation that aims to bridge the gaps in research knowledge that arise from using animals, are organoids. These are simplified, miniaturized models of human organs that are created by genetically altering cells, so they take on the identity of human cell types that are specific to certain organs.
In this work, the scientists created brain organoids that carried mutations that are known to cause Huntington's. While repeats in the HTT gene don't cause disease if there are fewer than 35 repeats, a greater number of repeats has been linked to Huntington's. The mutations cause neuronal death in the brain. As the number of repeats increases, the severity of the disease tends to get worse, explained co-corresponding study author Dr. Jakob Metzger of Heinrich Heine University Düsseldorf (HHU).
The Huntington's cerebral organoid model showed that the expression of CHCHD2 was abnormally low throughout different stages of development. The CHCHD2 reduction slowed the metabolism of neurons. CHCHD2 normally keeps mitochondria healthy, and has been previously implicated as a player in Parkinson's. This is the first time it's been linked to Huntington's. The researchers also determined that when CHCHD2 function was restored, the metabolism of neurons returned to normal.
"That was surprising," noted study co-author Selene Lickfett, a graduate student at HHU. "It suggests in principle that this gene could be a target for future therapies."
This study has shown that mutations in HTT also seem to disrupt the development of the brain long before Huntington's symptoms arise. This emphasizes the importance of early diagnosis, Lickfett added.
The organoids showed that defects arose in neural progenitor cells before toxic aggregates that are a hallmark of Huntington's arise. The pathology may start in patients long before it is detectable in the clinic.
Huntington's is generally thought to progress as mature neurons degenerate. But there might be changes occurring far earlier, and it may be possible to develop treatments for earlier stages, the researchers suggested.
"Our genome editing strategies, in particular the removal of the CAG repeat region in the Huntington gene, showed great promise in reversing some observed developmental defects. This suggests a potential gene therapy approach," said co-corresponding study author Professor Alessandro Prigione of HHU.
Increasing CHCHD2 expression could be another option too, said Prigione, who also added that these findings could have implications for neurodegenerative disease in general. Mitochondrial defects may present new avenues for treating those diseases.
Sources: Max Delbrück Center for Molecular Medicine, Nature Communications