Neurological Deficits of Angelman May Depend on microRNA Deficiency

Neurological Deficits of Angelman May Depend on microRNA Deficiency

The neurological deficits that characterize Angelman syndrome may be rooted in the insufficient production of a small RNA molecule, called miR-708, that leads to abnormal calcium-activated signals in the brain, according to a mouse study.

The study, “Down-Regulation of miRNA-708 Promotes Aberrant Calcium Signaling by Targeting Neuronatin in a Mouse Model of Angelman Syndrome,” was published in the journal Frontiers in Molecular Neuroscience.

Angelman syndrome is caused by the lack of or abnormal expression of the maternally inherited copy of the UBE3A gene, which provides instructions for cells to produce a protein known as ubiquitin protein ligase E3A. But how this genetic deficiency results in the developmental delays, intellectual disabilities, and motor impairments that mark the condition is poorly understood.

Now, researchers at India’s National Brain Research Centre sought to understand in detail the molecular mechanisms underlying Angelman symptoms.

There is mounting evidence that a specific type of genetic messengers, called microRNAs (miRNAs) play a role in many neurological disorders characterized by developmental problems, including autism, Rett syndrome, Down syndrome and fragile X syndrome.

miRNAs are short RNA molecules that do not code for proteins but instead target specific genes to turn off their activity.

Many studies in model organisms have shown that specific miRNAs play a significant part in cell growth, differentiation, and brain development in the embryo and after birth.

To discover miRNAs that could play key roles in Angelman syndrome, scientists searched for miRNAs that were changed in the brain of an Angelman mouse model and compared that with healthy mice.

The results revealed that a specific miRNA, called miR-708, was being produced at lower amounts in the brains of Angelman mice, compared to wild-type controls. miR-708 was reduced by 30% of its normal levels in the first days after birth and by 50% in adult mice.

Further biochemical and molecular studies showed that miR-708 targets a brain-specific protein called neuronatin, which appears to be key for brain development.

Neuronatin levels were significantly increased in various brain regions in Angelman mice while embryonic and soon after birth. This was consistent with the lower amounts of miR-708 observed in these mice, as this miRNA normally works to inhibit neuronatin expression.

The results revealed a potential cascade of effects in the brains of Angelman mice: a decrease in miR-708 levels leads to an increase in neuronatin levels, which results in abnormal regulation of calcium levels inside neurons.

In turn, this amplifies a type of calcium-activated signal that regulates many cellular pathways and is important for neurons to send messages to other neurons.

These observations were seen in the brains of Angelman mice and confirmed in mouse neurons maintained in laboratory cultures.

“These results indicate that miR-708/neuronatin mediated aberrant calcium signaling might be implicated in [Angelman disease mechanism],” researchers said.

Although it remains unclear why a deficiency in UBE3A affects miR-708 levels, this fundamental research study identified potential important molecular players in Angelman syndrome and can open up new avenues of investigation for better understanding of the disease.

Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
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Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
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