Page 16 - Abacoa Community News - May '21

Page 16, Abacoa
scieNce ON the cUttiNG edGe

The Scripps Research Institute News

Autism Gene Study Finds signaling at a high level, using a known growth hormone, might Page stresses that the study is preliminary, not grounds for
Widespread Impact To Brain’s rescue the brain undergrowth. off-label use of IGF-1 as a possible autism treatment. He’s often
“We thought that treating with insulin-like growth factor 1,
asked by families what they can do for their children diagnosed

Growth Signaling Network IGF-1, should increase the activity of the downstream signaling with autism. He suggests asking their doctor for a genetic testing
cascade, which should result in increased growth,” Levy says. as a first step.
Mutations to Dyrk1a gene lead to brain undergrowth; an After treating Dyrk1a mice from birth to day seven, she found “It helps with understanding of what’s going on, it allows
existing drug rescues the condition in newborn mice. that was the case. The observed microcephaly improved, and them to connect and find support, and also to be aware if clinical
Damage to the autism-associated gene Dyrk1a, sets off a under the microscope, the brain tissue showed normalized neuron trials begin,” Page says. “It’s too soon for affected families to go
cascade of problems in developing mouse brains, resulting in growth. to their pediatrician and say, ‘Give my child this.’ This is a first
abnormal growth-factor signaling, undergrowth of neurons, Toward Targeted Treatments step in evaluating whether a potential treatment could be used
smaller-than-average brain size, and, eventually, autism-like Based on those results, more investigation is warranted in the clinic.”
behaviors, a new study from Scripps Research, Florida, finds. on the potential for growth hormone treatment to benefit a In addition to Page and Levy, the authors of, “Dyrk1a
The study from neuroscientist Damon Page, Ph.D., describes minority of children with autism, those with Dyrk1a mutations, mutations cause undergrowth of cortical pyramidal neurons via
a new mechanism underlying the brain undergrowth seen in or related downstream mutations and manifestations, including dysregulated growth factor signaling,” in the journal Biological
individuals with Dyrk1a mutations. Page’s team used those microcephaly, Page says. Psychiatry include George Tsaprailis and Gogce Crynen of
insights to target the affected pathway with an existing medicine, Many questions remain. Whether IGF-1 treatment in the Scripps Research, Florida, and Christy LaFlamme of The Harriet
a growth hormone. It restored normal brain growth in the Dyrk1a newborn Dyrk1a mice might also improve autism-like behaviors L. Wilkes Honors College, Florida Atlantic University.
mutant mice, Page says. in the mice is still under investigation, Levy adds. Also, it’s still The study was funded through gifts and grants from Nancy
unclear whether there is a critical treatment window during Lurie Marks, the National Institutes of Health, and the RJ
mouse brain development, and if so, how large that window Foundation.
may be.
In humans, neural progenitor cells begin forming in the Crohn’s Disease May Develop
third week of pregnancy. By the seventh week, actual neuron
production starts. It’s a short window – neuron production in the From Warped Immune Cell
billions is mostly finished by around the 20th week of gestation. Signaling During Bile Acid
As neurons are made, each migrates to its final destination in
the forming brain. Once there, it starts making connections with Exposure
other neurons, elongating and branching out, literally wiring
the developing brain. Rapid brain development continues with Study reveals how T cells in the small intestine respond
experience and growth after birth. to bile acids, offering localized treatment direction for a
“As of now, there’s simply no targeted treatments available Autism is a constellation of disorders with multiple causes, cause of chronic illness.
for individuals with autism spectrum disorders caused by meaning that targeted, individualized treatments will be needed People with Crohn’s disease are typically treated with
DYRK1A mutations,” Page says. “This represents a first step in to assist people who seek them, Page says. Prevalence of autism powerful anti-inflammatory medications that act throughout
evaluating a potential treatment that could be used in the clinic.” diagnoses has been rising steeply since the 1990s. Research their body, not just in their digestive tract, creating the potential
Their study appears Thursday in the journal Biological from the U.S. Centers for Disease Control and Prevention now for unintended, and often serious, side effects. New research
Psychiatry. estimates 1 in 59 children have an autism spectrum disorder. The from the lab of Mark Sundrud, Ph.D., at Scripps Research,
To track the effects of missing Dyrk1a genes, Jenna Levy, mutations to Dyrk1a that cause autism appear to be sporadic, Florida suggests a more targeted treatment approach is possible.
the paper’s first author and a graduate student in Page’s lab, meaning they aren’t typically inherited, but rather appear
engineered mice to have one or two broken copies of Dyrk1a randomly, Page says. The Scripps Research Institute News on page 17
in their developing brain tissue. The brains of both sets of mice
developed abnormally, she found, displaying decreased brain
size and number of neurons, as well as reduced number of other
brain cells.
Downstream Effects
The scientists also conducted “unbiased” proteomic studies,
to see if the mutant mice had abnormally high or low levels of
other unknown proteins that might impact brain development.
Using a technique called “high-resolution tandem mass
spectrometry coupled to liquid chromatography,” they 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,
Levy says.
“The specific signaling cascades we found altered in Dyrk1a
mutants are implicated in multiple causal mechanisms of
autism,” Levy says.
A computational biology technique called ingenuity pathway
analysis helped them find altered proteins. There were changes
to those involved in nerve signaling, creation of synapses, and
growth of axons, the long, insulated extensions that give neurons
their distinct shape. Also, multiple forms of the protein Tau were
depleted in the Dyrk1a mice.
“These data implicate signaling cascades that were previously
not known to be altered by Dyrk1a mutations,” Page says.
Many Autism Genes
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.
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 one in 20, he says.
“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.”
Previously, Page’s lab has found autism-linked mutations to a
gene called Pten can cause an opposite effect, brain overgrowth,
or macrocephaly.
“What we didn’t know before is that the signaling disruptions
that cause microcephaly, brain undergrowth, appear to be the
flip side of the coin of the signaling disruptions that cause
macrocephaly, brain overgrowth,” Page says.
Because of that, they hypothesized that restoring growth