Abstract

Several neurodegenerative diseases including Alzheimer’s disease (AD) and frontotemporal dementia feature the accumulation of misfolded tau protein in vulnerable neurons in the brain. Using a novel human induced pluripotent stem cell (iPSC)-derived neuron model of tau aggregation, I have now identified several potential regulators of tau aggregation, including several RNA binding proteins that help regulate RNA stability and splicing. My work now suggests the mis-localization of these RNA-related proteins to tau aggregates may also trigger toxic changes in splicing that may lead to neurodegeneration. The proposed work will utilize several different model systems including in-depth human histopathologic and transcriptomic analyses, human iPSC-derived neuron studies, and biochemical assays to identify how RNA and RNA binding proteins affect tau aggregation and neurotoxicity. Ultimately, this work will provide much-needed insight into the cellular and molecular pathways that go awry in AD and other tauopathies and has the potential to identify novel therapeutic targets to slow or prevent these diseases.