Most cancers drug alters autism-like traits in mice | Spectrum
If repeated: Deletions of ASH1L cause excessive grooming in mice, which treatment with the cancer drug vorinostat is alleviated.
Mark Bowler / Science Source
A cancer drug that boosts gene expression reduces repetitive behaviors and improves memory and sociability in a mouse model of autism, according to a new study. However, the treatment did not improve the animals’ anxiety or motor problems.
The mice lack the autism-related gene ASH1L in their brains. The gene codes for an enzyme that helps regulate chromatin, or the clumps of DNA and proteins that make up chromosomes. Without the gene, the mice exhibit more repetitive behaviors and are less interested in socializing than control mice, according to a study published in June.
Loss of the gene in neurons also reduces the expression of other genes that are critical to early brain development, this study showed. The ASH1L enzyme increases gene expression by adding chemical tags to a histone – the protein DNA that DNA wraps around. In its absence, cells produce too much of another enzyme that suppresses such labeling.
For the new work, the same researchers blocked the enzyme with a drug called vorinostat (also known as SAHA) – which is often used to treat lymphoma – which causes gene expression to rise again.
“We think this SAHA inhibitor is a promising pharmacological treatment,” said lead researcher Jin He, assistant professor of biochemistry at Michigan State University in East Lansing.
It’s unclear whether the drug will prove helpful in autistic people, researchers say. Understanding exactly how the drug alters behavior is critically important, says Alex Nord, an adjunct professor of psychiatry at the University of California, Davis, who was not involved in the work.
“With these behavioral studies, I want to know why,” says Nord.
Social Interest: Heatmaps show how drug treatment (bottom row) increased interest in a different mouse (left panels) versus an object (right panels) in mice with an autism-related mutation.
Changes in behavior:
The researchers created mice that lacked both copies of ASH1L in their brains. (Mice lacking the gene all over their bodies die shortly after birth.) They then injected vorinostat into some mice daily for 10 to 60 days after birth and performed a series of behavioral tests.
In a social test, both wild-type and treated ASH1L mice preferred interacting with a new mouse over an object, while the untreated ASH1L mice showed no such preference. Treated ASH1L mice and controls also spent comparable time grooming themselves, while the untreated ASH1L mice over-grooming, which was viewed as analogous to the restricted and repetitive behaviors of some autistic people. And the treated ASH1L mice improved on a memory test, suggesting that the drug may improve cognitive abilities.
The results were published in Neuroscience Letters in September.
However, the drug did not change other properties: both the treated and untreated ASH1L mice grew more slowly and remained smaller than their wild-type counterparts. They also spent less time in an open field – a sign of fear – and closed their paws when held by the tail, a sign of muscle control problems.
The neural circuitry underlying the behaviors that changed with treatment might be more flexible after birth than the circuits associated with those who didn’t, he says. That means earlier treatment, maybe even prenatally, can make it possible to address these other characteristics, he says.
Unknown mechanism:
The behavioral improvements are “promising,” says Sofia Lizarraga, an assistant professor of life sciences at the University of South Carolina at Columbia, who was not involved in the work. But the drug blocks a wide range of enzymes and can have far-reaching effects on gene expression, which could cause undesirable side effects in humans, says Lizarraga.
Researchers should next test the drug in neurons derived from stem cells from people with ASH1L mutations to better understand how it works, she says. (In an unpublished paper, Lizarraga’s lab showed that a more targeted inhibitor improved structural impairments in neurons with ASH1L mutations.)
“The more we know about the cellular and molecular mechanisms that underlie behavior, the better we can personalize the therapies,” says Lizarraga.
It’s also not clear why such a general drug would cause specific behavioral changes in the mice, Nord says, raising doubts as to whether it would help autistic people as well.
“It’s a good study,” he says. “But I want to see more. I want to see mechanisms, I want to see specificity. “
The researchers plan to test whether treating the mice with the same drug shows the same effects sooner or later in life, and to study how long the effects last after treatment is stopped. They also want to test the drug in mice with mutations in other genes associated with autism that are involved in chromatin regulation.
Quote this article: https://doi.org/10.53053/VEQN7520
