Damage to Dyrk1a, in a mouse model, leads to abnormal growth-factor signaling, undergrowth of neurons, smaller-than-average brain size, and, eventually, autism-like behaviors, a new study from Scripps Research, Florida, finds. Further, the researchers showed that an existing growth hormone treatment, insulin-like growth factor 1 (IGF-1), restores normal brain growth in newborn mice of this same type.
Since Dyrk1a has been linked to autism spectrum disorder (ASD), this research could lead to new targets or putative treatments for ASD, which has no biological-based treatments to date and has very complex genetics. The study appears this week in the journal Biological Psychiatry.
Senior author Damon Page, PhD, said in a release, “As of now, there’s simply no targeted treatments available for individuals with autism spectrum disorders caused by DYRK1A mutations. This represents a first step in evaluating a potential treatment that could be used in the clinic.”
The CDC reports that 1 in 45 children in the US are diagnosed with ASD. The World Health Organization says the worldwide rate is about 1 in 270, but it is not known if higher rates of the disease are related to better diagnostic approaches or to other factors.
Drug repurposing is an attractive option, but it may be harder to implement in conditions such as ASD, which has been linked to 100s of genes and has a varied phenotype.
Page estimates that fewer than 1 percent of people diagnosed with autism spectrum disorder carry Dyrk1a mutations. Half of those show autistic behavioral traits, and about 70 percent have short stature. But many more people with autism diagnoses display microcephaly, or smaller-than-average head circumference, around 1 in 20, he says.
For their study, the team engineered mice to have one or two mutated copies of Dyrk1a in their developing brain tissue. The brains of both sets of mice developed abnormally, displaying decreased brain size and number of neurons, as well as reduced number of other brain cells.
Further, using a technique called “high-resolution tandem mass spectrometry coupled to liquid chromatography,” the researchers found that the Dyrk1a mutant mice had reduced levels of 56 cellular proteins, and increased levels of 33. Many of those were known autism risk genes, some implicated in sending growth signals, says Jenna Levy, the paper’s first author and a graduate student in Page’s lab.
“The specific signaling cascades we found altered in Dyrk1a mutants are implicated in multiple causal mechanisms of autism,” she adds.
At least 200 different high-confidence risk genes for autism spectrum disorders have been identified, Page says, but little has been known about their roles and relationships, complicating diagnosis and treatment development efforts.
“Importantly for treatment considerations, this study suggests there may be a point of convergence for multiple autism causes,” Page says. “Abnormal activity of this pathway appears to be shared across various genetic causes of autism, pointing to the possibility of common molecular target for therapeutics.”
Questions that remain include: Whether IGF-1 treatment in the newborn Dyrk1a mice might also improve autism-like behaviors? Also, it’s still unclear whether there is a critical treatment window during mouse brain development, and if so, how large that window may be.
Page stresses that the study is preliminary, not grounds for off-label use of IGF-1 as a possible autism treatment. He’s often asked by families what they can do for their children diagnosed with autism. He suggests asking their doctor for a genetic testing as a first step.
“It helps with understanding of what’s going on, it allows them to connect and find support, and also to be aware if clinical trials begin,” Page says. “It’s too soon for affected families to go to their pediatrician and say, ‘Give my child this.’ This is a first step in evaluating whether a potential treatment could be used in the clinic.”