Identification of the molecular mechanisms that ameliorate the progression of Huntington disease-like syndrome and age-dependent neuronal dysfunction

Brain function relies on communication between individual neurons. During ageing, gradual declines in cognitive function and memory are often associated with the loss of neurons. In devastated conditions, such as Huntington's disease and Alzheimer’s disease, neuronal death is rapid, leading to dementia.

In Singapore, dementia occurs in one out of 10 people aged 60 and above; this number is increasing in our rapidly ageing society. As there are currently no cures for any neurodegenerative condition, identifying a new therapeutic target is an urgent need for our society. In this study we tackle this challenge, with the goal of elucidating the molecular mechanisms underlying Huntington disease-like (HDL) syndrome, a condition that resembles Huntington's disease.

Specifically, we will: 1) functionally characterize the gene mutated in HDL2 (Junctophilin 3), focusing on neuronal function in young and aged animals, and 2) screen for genes that suppress the HDL2-linked phenotype using a forward genetic screen in Caenorhabditis elegans. We will use a combinatorial approach, taking advantage of genetic tools and mammalian cell biology to accomplish these aims. Results from these experiments will provide fundamental insights into how ageing leads to neuronal dysfunction, and reveal specific details about HDL2 that will help identify novel therapeutic targets for potentially curing Huntington's disease and other neurodegenerative conditions.