A Research Blog

New study discovers pervasive RNA changes in the epileptic brain

Epilepsy is the fourth most common neurological disorder afflicting over 60 million people worldwide. The disorder is characterised by a tendency to have recurring, unprovoked seizures, and can cause other health problems. While seizures can be in part controlled by medication, there is currently no effective cure for epilepsy.  More fundamental research is needed to better understand the disorder and to identify treatment targets.

DNA is a molecule that carries the genetic instructions used in the growth and function of all living organisms, while RNA is a molecule that, amongst other functions, is essential for the transmission and use of these genetic instructions. Both DNA and RNA are essential for all known forms of life.

Currently, most of the research in epilepsy is focused on mutations and variations in the DNA. However, other types of variations might occur specifically in the RNA, which is a process called RNA  editing. Hence, it may be important to examine both DNA and RNA variations in epilepsy. This new research shifts the focus from solely analysing DNA, to analysing RNA editing in the epileptic brain.

In a study published in Genome Research, Duke-NUS Medical School’s (Duke-NUS) Associate Professor Enrico Petretto examined the role of RNA editing in the brain and discovered a new disease mechanism for epilepsy. The study’s findings breathe new life into the field of RNA editing research and therapy development for epilepsy.

In our final Research Story of 2016, we shift our attention to neuroscience and ask Associate Professor Wang Hongyan, Interim Director of the Neuroscience and Behavioural Disorders Programme at Duke-NUS, for what she thinks is the biggest research story of 2016 to impact neuroscience research. Her pick, a home-grown story literally, is that of the midbrain organoid developed in Singapore by a team from Duke-NUS, A*STAR’s Genome Institute of Singapore and the National Neuroscience Institute.

Making Mini-brains

NBD 2016How does your brain interface so seamlessly with the world? …retain memories? …learn? …determine your personality? And, where does it all go so wrong with neuropsychological disorders? Due to the complexities of the brain and difficulties in accessing human brain tissue for research, these questions have eluded scientists for a long time. Now, researchers are a step closer to answering these questions, by growing brain organoids in the lab. Brain organoids are essentially mini-brains grown in a petri dish, and show remarkable similarity to human brains with the same neural cell populations, 3D architecture and connectivity.

Many scientists believe the major underlying cause of dementia is the accumulation of clumps of a protein called beta-amyloid, which is a hallmark of Alzheimer’s disease (AD). AD is the most common form of dementia, and it accounts for 60 to 80% percent of dementia cases. Apart from AD, there are many different types of dementia, including some rare types that are inherited or caused by mutations in certain genes. 

Recently, multiple missense mutations in the gene TRIAD3 that result in its loss-of-function have been identified in patients suffering from disorders characterised by cognitive decline, dementia, and movement disorders.  However, it was not clear how TRIAD3 dysfunction resulted in cognitive decline and dementia.

A study by Duke-NUS Assistant Professor Shawn Je, published in Aging Cell, focused on rare mutations in Gordon Holmes syndrome (GHS) patients; these individuals exhibit cognitive decline and dementia. Asst Prof Je’s work was able to show the causal relationship and underlying molecular mechanisms of how the loss-of-function of TRIAD3 resulted in protein misregulation in neurons which, consequently, resulted in synaptic problems and behavioural deficits.

TRIAD3A is an E3 ubiquitin ligase that recognises and facilitates the ubiquitination of its targets for degradation by the ubiquitin-proteosome system (UPS). Asst Prof Je’s laboratory previously identified that this protein regulates a key synaptic protein named Arc (activity-regulated cytoskeletal protein), thereby modulating synaptic transmission in neurons.

Antonius Van DongenAssociate Professor Antonius Van Dongen of the Neuroscience and Behavioural Disorders Programme at Duke-NUS Medical School is also Director of the SingHealth Advanced Bioimaging Core.Today, Dr Van Dongen shares with us more about microscopy and the Core's advanced bioimaging capabilities available to SingHealth and Singapore investigators.


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