Disrupted cell skeletons might clarify mind wiring adjustments in autism-linked situation | Spectrum
Mutations in TSC2, a gene linked to autism and a related condition called tuberous sclerosis complex, cause developing neurons to ignore chemical cues that help them connect, a new study suggests. The results could explain the altered wiring patterns observed in the brains of people with such mutations.
TSC2 mutations disrupt the formation of axons, the long neural projections that send electrical signals from one brain cell to another, previous research shows. Researchers have long attributed this faulty wiring to problems with mTOR, a signaling pathway that helps neurons synthesize proteins and other materials that they need to grow and form connections; without TSC2, mTOR runs amok.
However, in neurons derived from the skin of a person with tuberculous sclerosis, the mTOR signaling pathway is not hyperactive, according to the new study. Instead, the work implies another signaling protein: RhoA.
“We were very surprised,” says Timothy Gómez, professor of neuroscience at the University of Wisconsin-Madison, who led the new study. “We expected that all of this would be mTOR.”
RhoA helps neurons reshape an internal cytoskeleton as they expand axons towards other cells. Deletions or duplications of genes in the Rho signaling pathway are found in people with autism. Several genes in the autism related chromosomal region 16p11.2 also interact with RhoA.
“I’m pleased to see that many autism-related genes are now converging on RhoA, which actually makes a lot of sense,” says Lilia Iakoucheva, an adjunct professor of psychiatry at the University of California, San Diego, who was not involved in developing the Education. “The work is nice.”
Gómez’s team created glutamatergic cortical neurons that transmit excitatory signals in the brain using stem cells from an 18-year-old man with tuberous sclerosis and autism. The cells carried a TSC2 mutation that resulted in low TSC2 protein levels, but no changes in mTOR activity compared to control neurons.
The researchers placed these neurons between parallel lines made from Ephrin-A, a chemical that prevents wandering axons from going astray and misconnecting in the developing brain.
Axons from cells lacking a copy of TSC2 ignored the Ephrin-A boundaries, branching and growing uncontrollably. These axons also expanded further than those of control neurons, which grew in straight lines and strictly avoided the chemical.
A 2010 study showed that developing axons from neurons lacking a copy of TSC2 typically respond to Ephrin-A when first exposed to high doses of lysophosphatidic acid (LPA), a RhoA activator. Gómez’s team replicated this experiment using their own TSC2 neurons; the results suggest that TSC2 mediates axon growth via RhoA.
“If you give the cells enough LPA, RhoA shoots up and then axons collapse,” says Gómez.
He and his colleagues also constructed some of the TSC2 neurons to make more RhoA protein, and the developing axons grew as expected: they dodged Ephrin A lines and also responded to other guiding signals, suggesting the role of RhoA confirmed in the cell’s migration problems. The results appeared in Nature Communications on May 10.
“This is the first study I know of that has shown that an autism disorder causes these leadership errors,” says Gómez.
Timothy Gómez, University of Wisconsin-Madison
RhoA signal defects are associated with many autism-related conditions. Researchers should be careful about applying the new findings to these other disorders, however, says Mustafa Sahin, director of the Translational Neuroscience Center at Boston Children’s Hospital in Massachusetts. Sahin led the 2010 work and reviewed the new study prior to publication.
“Different genes can regulate the cytoskeleton and Rho activity in different ways,” he says. “In most of our work on tuberous sclerosis, loss of TSC has very different effects on one type of neural versus another.”
For example, a 16p11.2 deletion in neurons that release the neurotransmitter dopamine causes an increase in RhoA activity – the opposite of what Gómez’s team found, according to a May study by Sahin’s team.
And problems with mTOR and protein synthesis are obviously not the whole story in tuberous sclerosis either. “Most of us focus on protein synthesis, but we also believe that there are differences in the transcription of genes and in the cytoskeleton by RhoA,” says Sahin.
Everolimus, a drug that inhibits mTOR, is approved by the U.S. Food and Drug Administration for the treatment of seizures associated with tuberous sclerosis. On-going clinical trials are also testing rapamycin, an mTOR inhibitor, for treating benign tumors caused by the disease. “Future treatments may have to consider all of these different things that TSC regulates,” says Sahin, including RhoA.
Gómez and his colleagues looked at dynamic axon projections rather than neurons alone, says Karun Singh, an adjunct professor of medicine at the University of Toronto in Canada, who was not involved in the study. Other researchers should do the same, he says, as under-researched axon growth and its role in forming neural connections during development in autism research.
Gómez, whose father Manuel Rodríguez Gómez published the first textbook on tuberous sclerosis and established diagnostic criteria for the disease, wants to continue this work. His group plans to study the biochemical signals that link TSC2 directly to RhoA, using the same axon growth model.
“This is the most exciting work with human stem cells that comes out of my laboratory,” he says. “We very much hope that we can make further contributions.”
Quote this article: https://doi.org/10.53053/ELJV8487