Mechanisms of Dysregulated Translation in Human Neurons Carrying FTD-associated Tau Mutations

Protein synthesis is a vital biological process, important for neuronal development, synaptic plasticity, and cognitive functions such as learning and memory. In contrast, dysregulated translation is a feature of many neurodegenerative disorders, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Pathogenic changes to the microtubule associated protein tau are thought to cause neurotoxicity and dysfunction in both AD and FTD in part by disrupting several molecular processes, including protein synthesis. However, the molecular mechanisms by which pathogenic tau disrupts protein synthesis remain elusive. In this application, we will determine how FTD-associated heterozygous mutations in tau impact protein synthesis in human neurons. We will use human induced pluripotent stem cell (iPSC)-derived neurons carrying FTD-associated tau mutations as a model. The iPSCs will be differentiated into neurons using Neurogenin-2, a master transcription factor capable of inducing differentiation into excitatory neurons in under two weeks. Using this platform, in the first aim we will determine the impact of FTD-associated tau mutations on translation elongation rates and will perform ribosome profiling to determine the translatome and translational efficiency associated with the FTD- associated tau mutations. In the second aim, we will determine whether the tau mutations alter tau- ribosome interactions and if they cause ribosome collisions. These studies will provide insight concerning the mechanisms by which FTD-associated mutations in tau alters protein synthesis, as well as the biology and subsequent pathobiology of tau in tauopathies such AD and FTD. Project Number: 1R21AG093455-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Eric Klann | Institution: NEW YORK UNIVERSITY, NEW YORK, NY | Award Amount: $422,297 | Activity Code: R21 | Study Section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND] View on NIH RePORTER: https://reporter.nih.gov/project-details/11304417