| Autor: |
Patricia Rodriguez-Rodriguez, Luis Enrique Arroyo-Garcia, Lechuan Li, Christina Tsagkogianni, Wei Wang, Isabella Salas-Allende, Zakary Plautz, Angel Cedazo-Minguez, Subhash Sinha, Olga Troyanskaya, Marc Flajolet, Vicky Yao, Jean-Pierre Roussarie |
| Rok vydání: |
2022 |
| Popis: |
SUMMARYNeurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer’s disease. Here, we use a data-driven functional genomics approach to model ECII neuronsin silicoand identify the proto-oncogene DEK as a potential driver of tau pathology. By modulating DEK levels in EC neuronsin vitroandin vivo, we first validate the accuracy and cell-type specificity of our network predictions. We then show thatDeksilencing changes the inducibility of immediate early genes and alters neuron excitability, leading to dysregulation of neuronal plasticity genes. We further find that loss of function of DEK leads to tau accumulation in the soma of ECII neurons, reactivity of surrounding microglia, and eventually microglia-mediated neuron loss. This study validates a pathological gene discovery tool that opens new therapeutic avenues and sheds light on a novel pathway driving tau pathology in vulnerable neurons. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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