UC San Diego

The human brain is underpinned by a massive cellular complexity. A diverse conglomerate of cells, over 100 billion of them, functionally interact to power the most uniquely human organ. Unfortunately, the brain often encounters difficulties, and these neurological disorders drive significant clinical challenges. Most neurological disorders have no consistently effective therapeutic treatments. The work of this dissertation has been conducted with a single goal in mind: to improve the understanding of the human brain, in turn enabling the development of effective therapeutics to treat neurological disorders. To accomplish this, we conducted method development to enable effective single-nucleus profiling of the human brain, outlined tools for analyzing this data, carefully selected targets that may drive functional improvements, and developed and tested therapeutics capable of changing the brain. Here, we have profiled human brains with Down syndrome and matched controls to identify microglial overactivation, and a unique transcription factor, RUNX1, that appear to drive memory deficits. Additionally, we show that a potential therapeutic, targeting RUNX1, can reverse certain aspects of this biology. This work establishes a foundation for drug discovery, utilizing single-nucleus RNA-sequencing data to guide target selection and providing conceptual proof that these efforts can yield efficacious therapeutics.