Using cutting-edge technologies, researchers have shown how mutations in a gene called Transcription Factor 4 (TCF4) can lead to neurological disease. TCF4 has been associated with a variety of neuropsychiatric issues including autism spectrum disorders and schizophrenia. Scientists used miniature models of the human brain called organoids to study the impact of mutations in the TCF4 gene, and how to rescue them. The work has been reported in Nature Communications.
In this study, the researchers obtained samples from patients with Pitt-Hopkins Syndrome, which causes significant cognitive and motor impairments. Pitt-Hopkins Syndrome patients are typically non-verbal, and the disease is considered to be an autism spectrum disorder. The syndrome is known to be caused by TCF4 mutations.Transcription factors like TCF4 can influence the expression of many other genes, so mutations can have wide-ranging effects.
The researchers turned to an organic model because mouse models of Pitt-Hopkins have failed to recapitulate the symptoms that are observed in patients. Patient skin cells were genetically reprogrammed to create induced pluripotent stem cells, which were then used to generate brain organoids. The researchers could actually see the defects in the organoids caused by mutated TCF4 without a microscope, noted senior study author Alysson R. Muotri, Ph.D., a professor at the University of California San Diego School of Medicine.
Brain organoids carrying TCF4 mutations were smaller than unmated organoids, and the neurons were failing to develop properly, remaining as progenitor cells instead.
The researchers determined that when TCF4 was mutated, SOX genes were dysregulated, and the Wnt pathway was disrupted. Those biochemical signals are crucial to ensure that neurons develop, mature, multiply, and migrate to the right places in the brain. Since the population of neural progenitors failed to expand, there weren't as many cortical neurons in the organoid. Any mature neurons that were produced were not as excitable as healthy neurons, and sometimes failed to organize properly. Neural activity was disrupted in the mutant organoids.
The researchers suggested that the neurological disruptions in the organoids could lead to the problems seen in patients, and they were interested in rescuing them.
Two gene therapies were tested in the organoids, and both restored the expression of normal TCF4. The defects in the mutant organoids were corrected.
While this method could be useful, it would have to undergo a lot more testing before it was offered to patient families. Gene therapies for Pitt-Hopkins would also have to be applied at later stages than they were in these organoids, after patients were diagnosed. The research shows, however, that it may be possible to treat this disorder or others like it with some type of gene therapy.
Brain organoids that model TCF4 mutations could also be used now to provide new insights into other neuropsychiatric disorders.
Sources: University of California - San Diego, Nature Communications
