A Research Blog

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.

Through experimentation, this work confirmed that two of the missense mutations in TRIAD3 in GHS patients affected protein function and led to the misregulation of Arc protein and synaptic deficits.  Furthermore, the synaptic deficits that resulted from the loss of TRIAD3A function caused learning and memory deficits in mice. These findings suggest that the dementia observed in GHS patients is driven by the altered function of Arc resulting from the loss-of-function mutations in TRIAD3A.  This further suggests that modulating Arc protein levels or boosting TRIAD3 protein levels in neurons could potentially rectify synaptic transmission problems in certain types of dementia patients, and could be used as a therapeutic target to treat these patients. 

Loss of Triad3A in the Hippocampus leads to memory impairment in Morris Water Maze

Asst Prof Je and his team performed the Morris water navigation task (pictured above), which is widely used to study spatial learning and memory.  Mice were placed in a large circular pool and were required to find an invisible platform that allowed them to escape the water by using various cues. Once trained, the mice usually spent more time where the hidden platform (indicated by a white circle) was located (shown on the left), because they learned and memorised the location of the hidden platform.  In contrast, when Triad3 protein was removed in the specific brain area, the mice had a hard time remembering the location of the hidden platform and spent less time near the platform (shown on the right).

The study was supported by the Singapore Ministry of Education Tier 2 Grant (MOE2014-T2-2-071), the National Research Foundation Singapore under its Cooperative Basic Research Grant (NMRC/CBRG/0075/2014) and administered by the Singapore Ministry of Health’s National Medical Research Council, the Khoo Postdoctoral Fellowship Award (Duke-NUS-KPFA/2015/0001) and the Duke-NUS Signature Research Programme, with funding from the Ministry of Health.

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