A038 Systems modeling for gene-targeted homeostatic reprogramming of vulnerable striatal GABA-ergic neurons in Huntington’s disease

<h3>Background</h3> GABA-ergic neuron vulnerability in neurodegenerative diseases such as repeat expansion diseases (REDs) is poorly understood on a systems level. <h3>Method</h3> Using innovative systems modeling methods (network analysis Rando-SDS; shape deformation analysis Geomic v2) to leverage omics data from Huntington’s disease (HD) model knock-in (Hdh) mice and from wild-type aging mice, complemented by biological studies in mice and mutant Huntingtin flies, we study genes that in disease-vulnerable GABA-ergic neurons, the medium-spiny-neurons (MSNs) of the striatum, are dysregulated in Hdh mice and show changes in ribosome-associated mRNA levels or show ribosome-associated 3’ UTR accumulation in the aging mouse brain. <h3>Results</h3> We identified several categories of dysregulation that show CAG repeat dependence and that differ in Hdh mice at moderate compared to advanced behavioral symptom timepoints. <h3>Conclusion</h3> We will discuss how our studies may provide a molecular framework for investigating the use of homeostatic reprogramming as an early-stage strategy to render vulnerable GABA-ergic neurons and the neuronal circuits in which they function more resilient in REDs such as HD.