PATHOLOGICAL TAU IMPAIRS RIBOSOMAL FUNCTION AND DECREASES PROTEIN SYNTHESIS

Abstract

Alzheimer’s disease (AD) is one of 20 crippling neurodegenerative disorders characterized by the aberrant intracellular deposition of the microtubule-associated protein tau. One of the first symptoms of tauopathic patients is progressive memory loss and cognitive decline. Since the pathogenic mechanism by which tau induces neurotoxicity and leads to memory impairment is unknown, therapeutic strategies are limited. We performed subcellular fractionation of human AD and control brains coupled with tandem mass spectrometry peptide identification to identify tau-protein interactions. We performed cell free in vitro translation assays to measure translation of green fluorescent protein (GFP) in the presence of oligomeric proteins. Finally, we performed cell culture assays in immortalized lines and primary neuronal cultures to measure changes in protein translation as a result of pathological tau. We show that pathological tau associates differentially with endoplasmic reticulum (ER) proteins in AD compared to control brains. We also show that pathological tau associates with ribosomes in AD brains, and that this association leads to a decrease in overall translation as well as translation of vital synaptic proteins. Our data suggest that pathological tau impairs protein production. Since protein biosynthesis is necessary for memory formation, our work establishes a direct link between tau aberrations and memory impairment. We also show that there is a decrease in translation of synaptic proteins, which could be a reason for neuronal dysfunction observed in diseased brains. These data support the exploration of the tau-ribosome complex for therapeutic target identification, and it opens a new window of treatment strategies for tauopathies.