Congratulations to Gabbe Zuniga on her first author publication in Alzheimer’s & Dementia!
Congratulations to Gabbe Zuniga and the Frost lab on their publication! Gabbe is an MD/PhD candidate in the lab of Dr. Bess Frost with the Sam and Ann Barshop Institute for Longevity and Aging Studies.
Tau-induced deficits in nonsense-mediated mRNA decay contribute to neurodegeneration
Gabrielle Zuniga, Simon Levy, Paulino Ramirez, Jasmine De Mange, Elias Gonzalez, Maria Gamez, Bess Frost.
Alzheimer’s & Dementia. 2022;1-16. https://doi.org/10.1002/alz.12653
Introduction: While brains of patients with Alzheimer’s disease and related tauopathies have evidence of altered RNA processing, we lack a mechanistic understanding of how altered RNA processing arises in these disorders and if such changes are causally linked to neurodegeneration.
Methods: Using Drosophila melanogaster models of tauopathy, we find that overall activity of nonsense-mediated mRNA decay (NMD), a key RNA quality-control mechanism, is reduced. Genetic manipulation of NMD machinery significantly modifies tau-induced neurotoxicity, suggesting that deficits in NMD are causally linked to neurodegeneration. Mechanistically, we find that deficits in NMD are a consequence of aberrant RNA export and RNA accumulation within nuclear envelope invaginations in tauopathy. We identify a pharmacological activator of NMD that suppresses neurodegeneration in tau transgenic Drosophila, indicating that tau-induced deficits in RNA quality control are druggable.
Discussion: Our studies suggest that NMD activators should be explored for their potential therapeutic value to patients with tauopathies.
Keywords: Alzheimer’s disease, Drosophila, neurodegeneration, nonsense-mediated mRNA decay, nucleus, tauopathy