| Project Detail |
"The intraneuronal somatodendritic ""missorting"" and aggregation of Tau are pathological hallmarks in neurodegenerative diseases (NDDs) like and Alzheimers disease (AD), and are thought to be drivers of neurotoxicity. That NDDs manifesting with Tau ""missorting"" present with (neuro)metabolic abnormalities, often prior to pathology onset, is largely overlooked. EnergizeTau investigates the ground-breaking new idea that the somatodendritic re-sorting of Tau is a physiological response to bioenergetic challenges faced by excitatory neurons, such as hyperexcitation or energy deprivation. In its proposed role as modulator of neuronal energy management, Tau modulates the cellular energy demand through molecular interactions with key cellular functions, e.g. synaptic activity, ATP production and protein translation, and alters the neuronal metabolism. Continued energetic stress in disease results in irreversible ""silencing"" and Tau aggregation in affected neurons. Using my uniquely broad Tau expertise, we decipher how Tau interferes with energy demanding cellular functions to modulate neuronal energy household downstream of bioenergetic stress. Light-induced Tau expression and CRISPR-edited human neurons enable to study Taus molecular actions by interactomics and single-molecule imaging, and the effects on cellular functions. Taus influence on the neuronal metabolism is determined by longitudinal live cell metabolite imaging and spatial transcriptomics in human brains, and the impact on gene and chromatin regulation by Cut&Tag and DNA-FISH. Whether stressors converge on energy limitation as a driver of Tau re-sorting is assessed by high-content metabolite imaging. EnergizeTau introduces the metabolic component of Tau (patho)biology and generates a paradigm shift in NDD research. It creates space for re-thinking hallmark protein pathology in NDDs, and has the potential to result in new approaches targeting the neuronal energy metabolism to prevent and treat NDDs." |
