Project Title: Exosomes and miRNAs in Huntington's disease patient-derived iPSC-choroid plexus epithelial cells and cerebrospinal fluid
Huntington’s disease is a devastating, inherited, neurodegenerative disorder that causes psychiatric, cognitive, and movement deficits. It is caused by a mutation in the Huntingtin gene and results in chronic expression of the mutant Huntingtin protein (mHTT), which causes cellular dysfunction and selective neuronal death. Despite many animal studies and clinical trials to identify disease-modifying therapies, efforts are challenged by a relative lack of biomarkers to predict disease onset and progression. The potential cellular dysfunction, including early and reproducible alterations in gene expression, may be modulated by altered profiles of micro RNAs (miRNAs), which are small regulatory RNAs synthesized in cells and distributed throughout the brain via the secretion of exosomes into the cerebrospinal fluid (CSF) – the fluid that bathes the central nervous system. My project is focused on investigating altered miRNA expression within cells and CSF exosomes using HD patient-specific CSF biopsy assays and induced pluripotent stem cell-derived choroid plexus epithelial cells – the cells that produce the majority of the CSF. miRNAs are not randomly incorporated into exosomes and potential modes for the sorting of exosome miRNAs have been proposed. We hypothesize that the selective incorporation of miRNAs into exosomes is deficient in cells that express mHTT, and that this may result in altered exosomal miRNA profiles in HD patients. Our goal is to elucidate potential miRNA-based biomarkers and novel therapeutic targets to facilitate the treatment of this devastating disease.