New Frost lab publication in Alzheimer's & Dementia
Tau-induced deficits in nonsense-mediated mRNA decay contribute to neurodegeneration is now available online as a featured article in Alzheimer's & Dementia. Our study was also featured in several news outlets, including GEN: Genetic Engineering and Biotechnology News. We are incredibly proud of first author Gabrielle Zuniga and co-authors Simon, Paul, Jasmine, Elias, and Maruca!
Cells utilize the nonsense mediated RNA decay (NMD) pathway for post-transcriptional control of gene expression and degradation of faulty transcripts which, if translated, could potentially produce toxic proteins. In the current study, we find that pathological tau, a protein that accumulates in Alzheimer’s disease and related “tauopathies,” causes a toxic deficit in NMD. We find that overall NMD activity is reduced in the brain of Drosophila models of tauopathy based on a fluorescent reporter of NMD activity and quantification of transcripts known to be cleared by NMD. We further demonstrate that genetic manipulation of NMD core machinery significantly modifies tau-induced neurotoxicity in Drosophila, indicating that tau-induced deficits in NMD causally contribute to neurodegeneration. Mechanistically, we find that genetically increasing NMD clears polyadenylated (polyA) RNA from tau-induced invaginations of the nuclear envelope, and that genetically decreasing RNA export restores the ability of NMD to effectively clear its targets in brains of tau transgenic Drosophila. Finally, we find that treatment of tau transgenic Drosophila with a pharmacological activator of NMD restores NMD activity and suppresses tau-induced neurodegeneration. Taken together, we have discovered a critical deficit of NMD, a safeguard of the transcriptome, in tauopathy, and that tau-induced increase of RNA export, limited NMD, and neurodegeneration are mechanistically linked and pharmacologically targetable.