Single Cell Profiling of Brain Tissue and Stem Cell Models of Tauopathy
The goal of this project is to understand both the gene expression and cellular changes that lead up to the onset of tauopathy, as well as the changes that occur after the disease has already started. We will carry out single cell sequencing on forebrain organoids derived from MAPT mutation patient stem cells to identify cell-specific gene expression changes that occur very early in brain development prior to disease later in life. We will assay specific cellular phenotypes such as mitochondrial function and tau accumulation to assess the health and function of neurons in these models. We will also sequence human brain tissues with the same mutations to characterize gene expression changes occurring late in disease, and see how this compares with organoids.
We are using cutting edge sequencing and visualization technologies to study specific MAPT mutations that cause tauopathy by changing the tau 4R:3R ratio. These mutations have not been studied in cell culture systems before. By using these mutations, we will be able to increase the expression of 4R tau in vitro, which is usually high in human brain but low in cell culture neurons. This will also be the first investigation of gene expression changes in human brain tissue from carriers of these specific mutations, and we will generate data from multiple individuals across several brain regions. Once this study is complete, we will have identified novel mechanisms and pathways that lead to the development of tauopathy, which can therefore be therapeutically targeted for intervention prior to disease onset or neurodegeneration. We will be generating a rich and detailed dataset from both organoid models and human brain tissue that will be made publicly available for other researchers to access and analyze, which will further our understanding of how MAPT mutations cause tauopathy, and consequently the discovery and development of new treatments.