Charlene Smith-Geater, PhD

, Leslie Thompson, PhD

Modulation of E3 SUMO-ligase PIAS1 in 3D cortico-striatal assembloids and investigation of theHD relevant CSF SUMO-ome

Recent news of HTT lowering trials pausing has reinforced the need to pursue alternative or complementary therapeutic avenues. In the Thompson lab, we have been working on an alternative therapeutic approach, reducing the amount of a protein, PIAS1, in the brain. Two different HD mouse models and stem cells derived from HD patient skin cells were evaluated for the effect of altered PIAS1. PIAS1 plays a role in attaching proteins, called SUMO, to other proteins which changes how they behave and how well they carry out their cellular tasks. Our data shows thi sprocess is disrupted in HD. Our work has shown there is potential benefit for reducing PIAS1 in the striatum (in mice)and in human cells and we seek to explore this further in an even more relevant human model. I will work with HD patient stem cells, in which we have reduced the amount of PIAS1, and make them into 3D structures called organoids that resemble areas of the brain, the striatum and cortex (both affected in HD). I will then investigate cellular processes that we know are disrupted in HD, including somatic repeat instability, and see if reducing the amount of PIAS1 is beneficial. These studies include investigating the function and structure of the powerhouses that generate energy for the cells (mitochondria), how the cells communicate with each other (synapses), how well the cell repairs its DNA and whether the cells are expressing the correct genes. Additionally, I will examine HD patient cerebrospinal fluid (CSF) to determine levels of SUMO protein and what proteins it has been attached to or is interacting with. These CSF studies are aimed to help us understand more about what goes wrong in HD and may provide clues to a new therapeutic readout when testing how well drugs work for patients.