Investigating the mechanisms underlying abnormalities in neuronal activity through human pluripotent stem cell-derived microglia-sufficient brain organoids in Huntington’s disease

Microglia are the immune defense cells located within the brain and also play a big role in the maintenance of a healthy brain by scavenging and removal of damaged/unnecessary neurons and synapses. This “synaptic pruning” function is important for the proper developmental wiring of the brain. Huntington’s disease is a disorder of the brain, which gets worse over time. It is caused by DNA repeat expansions in Huntingtin gene leading to neuron cell toxicity and death. Of late, the role of microglia in Huntington disease development has been gaining momentum. I plan to study the effects that different DNA repeat sizes in Huntingtin gene have on the disease progression, through the repeats’ influence on the microglia’s behaviour and function as well as on the neurons’ reaction to synaptic pruning. Further, I will check if correcting either microglia/neurons or both would be useful in reducing the cellular symptoms of Huntington’s. The results will throw light on early development changes (influenced by different sizes of DNA repeats) that would occur in Huntington’s disease and also reveal how they impact a disease like Huntington’s, which usually affects patients late in their life.