UC Irvine

Stress granules (SGs) are membraneless organelles that form in response to cellular stress. Chronic cellular stress associated with neurodegenerative disease results in the persistence of SG structures. Chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of Huntington’s disease (HD) neuropathology. For my dissertation, I investigated localization and levels of the SG nucleating protein G3BP1 and found a significant increase in the density of G3BP1-positive SGs in the cortex and hippocampus of R6/2 transgenic mice, as well as in the superior frontal cortex of HD patient brains. I also examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of HD patients and show that a subset of their target mRNAs is differentially expressed in the prefrontal cortex of HD patients. Of these targets, there is an enrichment of SG components, including G3BP1. These findings suggest that SG dynamics might play a role in the pathophysiology of HD. Lastly, because the majority of the CSF is produced by choroid plexus epithelial cells, and a significant portion of CSF EVs likely originate from CPECs, I initiated the generation induced pluripotent stem cell (iPSC)-derived CPECs from HD and control lines that will allow for future mechanistic studies of EV secretion. Together, my work provides evidence of a potential role for CSF EV miRNAs in the regulation of SGs, identifies specific miRNAs that modulate the SG component G3BP1, and demonstrates feasibility for the generation of an iPSC-derived CPEC model.