Mutations in genes associated with autism cause a number of problems in mouse brain development

Autism-related Dyrk1a gene damage triggers a number of problems in mouse brain development, resulting in abnormal growth factor signaling, neuronal undergrowth, less-than-average brain size, and ultimately autism-like behavior, a new study from Scripps Research in Florida finds.

A study by neuroscientist Damon Page, Ph.D., describes a new mechanism underlying brain regrowth seen in people with Dyrk1 mutations. Peig’s team used these insights to target the affected path with an existing drug, growth hormone. It restored normal brain growth in Dyrk1a mutated mice, Page says.

As of now, there are simply no targeted treatments available for people with autism spectrum disorders caused by DYRK1A mutations. This represents the first step in assessing potential treatment that could be used in the clinic. “

Damon Page, Ph.D., Neuroscientist

Their study was published Thursday in the journal Biological psychiatry.

To track the effects of missing Dyrk1a genes, Jenna Levy, the first author and graduate student in Page’s lab, constructed mice to have one or two broken copies of Dyrk1a in their developing brain tissue. The brains of both sets of mice developed abnormally, showing reduced brain size and the number of neurons, as well as a reduced number of other brain cells.

Downstream effects

The scientists also conducted “unbiased” proteomic studies, to determine if the mutated mice had abnormally high or low levels of other unknown proteins that could affect brain development. Using a technique called “high-resolution tandem spectrometry in conjunction with liquid chromatography,” they found that mutated Dyrk1a mice had decreased levels of 56 cellular proteins and increased levels of 33. Many of them were known genes for autism risk, some involved in sending growth signals, Levy says.

“The specific signaling cascades we found altered in Dyrk1a mutants are involved in multiple causal mechanisms of autism,” Levy says.

A computer biology technique called Ingenious Pathway Analysis helped them find the altered proteins. There have been changes in those involved in neural signaling, synapse formation and axon growth, long, isolated extensions that give neurons their different shape. Also, multiple forms of Tau protein have been depleted in Dyrk1a mice.

“This data implies signaling cascades that were not previously known to be altered by Dyrk1a mutations,” says Page.

Many genes for autism

At least 200 different high-confidence risk genes have been identified for autism spectrum disorders, Paige says, but little is known about their roles and links, complicating efforts in diagnosis and treatment development.

It is estimated that less than 1 percent of people diagnosed with autism spectrum disorder carry Dyrk1a mutations. Half of them show autistic behavioral traits, and about 70 percent have low growth. But many more people diagnosed with autism have microcephaly or less than average head circumference, about 1 in 20, he says.

“Most importantly for treatment consideration, this study suggests that there may be a point of convergence for multiple causes of autism,” Page says. “Abnormal activities this time appear to share different genetic causes of autism, suggesting the possibility of a common molecular target for therapy.”

Previously, Page’s Laboratory discovered that mutations in a gene called Pten linked to autism can cause the opposite effect, excessive brain growth or macrocephaly.

“What we didn’t know before was that the signaling disorders that cause microcephaly, the undergrowth of the brain, seem to be the other side of the inhibition of the signals that cause macrocephaly, the excessive growth of the brain,” says Page.

Therefore, they hypothesized that restoring growth signaling at a high level, using a known growth hormone, could save brain undergrowth.

“We thought that treatment with insulin-like growth factor IGF-1 should increase the activity of the downstream signaling cascade, which should result in increased growth,” Levy says. After treating Dyrk1a mice from birth to day 7, she found this to be the case. The observed microcephaly improved, and under the microscope the brain tissue showed normalized neuronal growth.

According to targeted treatments

Based on these results, more investigations into the possibility of growth hormone treatment in favor of a minority of children with autism, children with Dyrk1a mutations or related mutations and manifestations downstream, including microcephaly, are justified, Paige says.

Many questions remain. Whether IGF-1 treatment in newborn Dyrk1a mice could also improve behavior in autism-like mice is still under investigation, Levy adds. Also, it is still unclear whether there is a critical window for treatment during mouse brain development and if so, how large that window may be.

In humans, neuronal progenitor cells begin to form in the third week of pregnancy. By the seventh week, the actual production of neurons begins. The window is short – the production of neurons in the billions is mostly completed around the 20th week of gestation. As neurons are created, each migrates to its final destination in the brain it forms. Once there, it begins to make connections with other neurons, to extend and branch out, literally connecting the developing brain. Rapid brain development continues with experience and growth after birth.

Autism is a constellation of multi-cause disorders, which means that targeted, individualized treatments will be needed to help people who are looking for them, says Paige. The prevalence of autism diagnoses has risen sharply since the 1990s. A study by the U.S. Centers for Disease Control and Prevention now estimates that 1 in 59 children has an autism spectrum disorder. Dyrk1a mutations that cause autism appear to be sporadic, meaning they are not usually inherited, but occur by accident, Paige says.

Emphasizes that the study is preliminary and not the basis for the misuse of IGF-1 as a possible treatment for autism. Families often ask him what they can do for their children diagnosed with autism. As a first step, he suggests asking their doctor for genetic testing.

“It helps them understand what’s going on, allows them to connect and find support, as well as be aware of whether clinical trials are starting,” says Paige. “It’s too early for affected families to go to their pediatrician and say, ‘Give this to my child.’ This is the first step in assessing whether potential treatment could be used in the clinic. “

Source:

Scripps Research Institute

Journal reference:

Levy, JA, and others. (2021) Dyrk1a mutations cause undergrowth of cortical pyramidal neurons through unregulated growth factor signaling. Biological psychiatry. doi.org/10.1016/j.biopsych.2021.01.012.

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