New work from the Frost lab published in Neuroscience!


This project was led by Lulu Schulz with the help of Paul Ramirez, Adrienne Lemieux, Elias Gonzalez, and Dr. Travis Thomson.


Lulu’s study was based on our recent finding that pathogenic forms of tau limit the extent to which "faulty" RNAs are cleared from the cell via nonsense-mediated RNA decay. In addition to targeting error-containing RNAs, nonsense-mediated RNA decay regulates the steady state transcript levels of some immediate early and activity-dependent genes, including ARC. ARC is very cool (to us) in that it contains a retrotransposon-derived gag domain (jiving nicely with our previous work on tau and transposable elements), which allows it to form capsids and transfer RNA between cells. While ARC is elevated in brains of patients with Alzheimer's disease and genetic variants in ARC increase susceptibility to Alzheimer’s disease, mechanistic insight into the role of ARC in Alzheimer’s disease was previously lacking. Using a Drosophila model of tauopathy, we find that pathogenic tau significantly increases multimeric species of the Drosophila homolog of ARC, Arc1, in the adult fly brain. We see that Arc1 protein is elevated within nuclei and the neuropil of tau transgenic Drosophila, but does not localize to synaptic vesicles or presynaptic terminals. We find that genetic manipulation of Arc1 modifies tau-induced neurotoxicity, suggesting that tau-induced Arc1 elevation causally mediates neurodegeneration. Overall, our work presents new insights into how retroviruses integrated into the host genome are co-opted by endogenous genes and can negatively impact cellular function as a consequence of pathogenic tau.


We are looking forward to the next phase of this project as Masters student Lulu stays with us for her PhD. Also, big shout out to Dr. Travis Thomson at the University of Massachusetts Medical School! He is such a fun and interesting collaborator who brings so many ideas and new resources to the table.


https://www.sciencedirect.com/science/article/pii/S0306452222001993