New work from Frost lab MD/PhD student Dr. Gabrielle Zuniga provides new insights into the effects of pathogenic forms of tau on RNA translation

Head over to bioRxiv to read about it: biorxiv.org/content/10.110...

We have previously shown that RNAs accumulate within nuclear envelope invaginations in tau transgenic Drosophila (and have now seen this in various other model systems of tauopathy as well): https://doi.org/10.1111/acel.12847

Gabbe previously reported that error-containing RNAs are not properly cleared via nonsense-mediated RNA decay in settings of tauopathy, and that such RNAs are translated into protein that also accumulates within nuclear envelope invaginations: https://doi.org/10.1002/alz.12653

In the current study, Gabbe found an overall increase in translation at early stages of tauopathy (but not later in the disease course) in Drosophila, and that active translation indeed occurs within nuclear envelope invaginations. With much help from collaborators Dr. Sakie Katsumura and Dr. Masahiro Morita, Gabbe performed polysome profiling from heads extracts of control and tau transgenic Drosophila and found preferential translation of specific RNAs that had previously been linked to neurodegeneration (polysome profiling from adult Drosophila heads was a very difficult but ultimately successful endeavor that required ridiculous numbers of fly heads – 10/10 do not recommend). Unexpectedly, Gabbe found that increasing nonsense-mediated RNA decay (which suppresses tau neurotoxicity) or exposure to rapamycin (which also suppresses tau neurotoxicity) further elevates the global translation rate in tau transgenic Drosophila, suggesting that elevated rates of mRNA translation are an early adaptive mechanism to limit neurodegeneration.

Thanks to all other coauthors: Jasmine De Mange, Paulino Ramirez, and Dr. Farzaneh Atrian, and funding from the National Institute on Aging (NIA).