MANY NEURO DISORDERS HAVE COMMON MOLECULAR CAUSE
Neurodevelopmental
disorders such as Down syndrome and autism-spectrum disorder can have profound,
lifelong effects on learning and memory, but relatively little is known about
the molecular pathways affected by these diseases. A study published by Cell
Press October 9th in the American
Journal of Human Genetics shows that neurodevelopmental disorders caused by distinct genetic
mutations produce similar molecular effects in cells, suggesting that a
one-size-fits-all therapeutic approach could be effective for conditions
ranging from seizures to attention-deficit hyperactivity disorder.
"Neurodevelopmental
disorders are rare, meaning trying to treat them is not efficient," says
senior study author Carl Ernst of McGill University. "Once we fully define
the major common pathways involved, targeting these pathways for treatment
becomes a viable option that can affect the largest number of people."
A large fraction of
neurodevelopmental disorders are associated with variation in specific genes,
but the genetic factors responsible for these diseases are very complex. For
example, whereas common variants in the same gene have been associated with two
or more different disorders, mutations in many different genes can lead to
similar diseases. As a result, it has not been clear whether genetic mutations
that cause neurodevelopmental disorders affect distinct molecular pathways or
converge on similar cellular functions.
To address this
question, Ernst and his team used human fetal brain cells to study the
molecular effects of reducing the activity of genes that are mutated in two
distinct autism-spectrum disorders. Changes in transcription factor 4 (TCF4)
cause 18q21 deletion syndrome, which is characterized by intellectual
disability and psychiatric problems, and mutations in euchromatic histone
methyltransferase 1 (EHMT1) cause similar symptoms in a disease known as 9q34
deletion syndrome.
Interfering with the
activity of TCF4 or EHMT1 produced similar molecular effects in the cells.
Strikingly, both of these genetic modifications resulted in molecular patterns
that resemble those of cells that are differentiating, or converting from
immature cells to more specialized cells. "Our study suggests that one
fundamental cause of disease is that neural stem cells choose to become full
brain cells too early," Ernst says. "This could affect how they
incorporate into cellular networks, for example, leading to the clinical
symptoms that we see in kids with these diseases."
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