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.