HDAC Inhibitors May Be Potential Treatment for Angelman Syndrome, Mouse Study Suggests

Iqra Mumal, MSc avatar

by Iqra Mumal, MSc |

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maternal genetic defects

Researchers at the National Brain Research Centre in India have shown that inhibitors of the proteins HDAC1/2 might be a potential therapeutic for the treatment of Angelman syndrome (AS) as increased activity of the HDAC1/2 causes brain dysfunction and behavioral issues in mice with AS.

The study, “Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome,” was published in the journal Neurobiology of Disease.

Genetic studies have established that Angelman syndrome is caused by deficits in the protein E3 ubiquitin ligase, which is involved in protein degradation within cells. People inherit two copies of every gene, one from the father and one from the mother, which are present on two alleles. The deficit in E3 ubiquitin ligase in patients with AS is caused by a defect in the UBE3A gene that is inherited from the mother. The father’s allele is turned off by the epigenetic mechanisms in our cells, which are involved in turning genes on and off.

HDACs (histone deacetylase proteins), are involved in gene expression by de-acetylating (removing an acetyl group from) histones, the proteins that DNA are wrapped around. By de-acetylating histones, the DNA becomes wrapped around the histones more tightly, which turns genes off.

A disease similar to Angelman syndrome, called Prader-Willi syndrome, has different acetylation patterns on histones compared to normal patients. Therefore, researchers wanted to explore whether acetylation levels were also different in Angelman syndrome.

Researchers used mouse brain cells and mouse models of AS that were deficient in the protein UBE3A in order to study this disease.

Results from this study show that a deficiency of UBE3A in mouse brains led to increases in levels of HDAC1/2, which subsequently caused a decrease in acetylation of histones in the brain. Even a partial decrease of UBE3A in mouse brain cells led to an increase in HDAC1/2 and a decrease in acetylation of histones.

This observation led researchers to determine whether sodium valproate, an HDAC inhibitor, could be used as a treatment for this disease. They showed that the HDAC inhibitor led to an increase in UBE3A in the brain cells of normal mice, but not in mice with AS.

Interestingly, the use of HDAC inhibitors led to an improvement in learning and memory-related behavioral deficits of Angelman syndrome mice as well as in motor skills.

The authors concluded the study by conveying that increases in HDAC1/2 in mice with AS might lead to dysfunction of the brain and behavioral abnormalities in mice. They also said that HDAC inhibitors could possibly be a potential treatment for Angelman syndrome.