Dysregulation of memory‐induced protein synthesis in tauopathies
Harrison Tudor Evans, Srinidhi V Kalava, Astra Yu, Drew Adler, Jessica Alapin, Mauricio M Oliveira, Eric Klann- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Protein synthesis is a vital biological process, important for many neuronal and cognitive processes such as synaptic plasticity and the formation, updating, and extinction of long‐term memories. Recent studies have identified dysregulated translation as a molecular hallmark of many neurodegenerative diseases, including tauopathies such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and corticobasal degeneration (CBD) (Evans et al., EMBO J, 2019; Evans et al., Acta Neuropathoc Comms, 2021; Elder et al., Commun Biol. 2021). This dysregulation of protein synthesis is thought to be driven in part by pathogenic alterations to tau, a neuronally enriched microtubule binding protein.
Method
Here, we have utilized a series of de novo proteomic analyses, including in vivo non‐canonical amino acid (NCAA) tagging, surface sensing of translation‐based ribosome speed of elongation (SunRiSE), and polysome profiling, to explore both in vitro and in vivo how mutant human tau alters translation in a variety of tauopathies models, including the PS19 mouse strain, human neurons from a FTD patient‐derived inducible pluripotent stem cells (iPSCs) line, as well as in transfected HEK293 cells.
Result
Using these techniques, we have found that both P301S and V337M mutant human tau can severely impair protein synthesis, even when protein degradation is inhibited. Our data also suggests that the dysregulated translation is caused, at least in part, by impaired elongation, with SunRiSE assays showing that P301S and V337M mutant human tau both slow elongation rates. We also have demonstrated that FTD‐mutant tau impairs protein synthesis in CA1 hippocampal neurons in PS19 mice and are determining whether learning‐induced increases in hippocampal protein synthesis following contextual fear conditioning are impaired in these mice.
Conclusion
Together, our results demonstrate that FTD‐mutant tau can severely impact several important components of the cellular translational machinery. Furthermore, our results also contribute to the growing evidence that impairments in protein synthesis are a feature of neurodegenerative diseases. This work was supported by the Alzheimer’s Association (H.T.E), Leon Levy foundation (H.T.E.), the Rainwater foundation (H.T.E.) and NIH grant NS121786 (E.K.).