Project 461766

The 15q13.3 deletion is a neurodevelopmental disorder (NDD) that manifests early during postnatal life and is associated with epilepsy, schizophrenia, autism spectrum disorder and developmental delay. It is a genetic disorder caused by the loss of a small piece of genetic material (DNA), and occurs in ~1 in 40,000 individuals, with recent predictions suggesting a higher incidence (~1 in 5,500). The genomic region affected contains ~10 genes. There are no treatments, and impairments experienced by individuals cause life-long disabilities. We identified that one of the ten genes (OTUD7A) may be responsible for mediating the major clinical outcomes. Further, emerging genetic studies indicate that OTUD7A is an independent neurodevelopmental and psychiatric risk gene; therefore, understanding its function in the brain is important to learn about how brain disorders arise. To examine OTUD7A, we performed a screen to identify which proteins interact with OTUD7A, and revealed that it regulates signaling molecules through protein homeostasis, which is the regulation of protein levels, localization and activity in neural cells. In this project, we will map the precise network of proteins regulated by OTUD7A in neurons to understand how its loss in the 15q13.3 deletion impairs brain development. We will also examine whether the loss of OTUD7A impairs axonal and synaptic development, or earlier deficits in neural stem cell or neuronal migration regulation, using mouse and patient stem cell-derived 2D and 3D organoid models. We hypothesize that abnormal protein homeostasis contributes to early and late neuronal deficits, leading to cognitive and behavioral deficits. We will also test a viral gene therapy strategy to restore OTUD7A function. These studies could reveal one of the first therapeutics for this NDD, and pave the way for developing gene therapies for the many other NDDs involving the loss/gain of DNA.