Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis

Abstract

One of the most common symptoms of Alzheimer's disease (AD) and related tauopathies is memory loss. The exact mechanisms leading to memory loss in tauopathies are not yet known; however, decreased translation due to ribosomal dysfunction has been implicated as a part of this process. Here we use a proteomics approach that incorporates subcellular fractionation and coimmunoprecipitation of tau from human AD and non-demented control brains to identify novel interactions between tau and the endoplasmic reticulum (ER). We show that ribosomes associate more closely with tau in AD than with tau in control brains, and that this abnormal association leads to a decrease in RNA translation. The aberrant tau-ribosome association also impaired synthesis of the synaptic protein PSD-95, suggesting that this phenomenon contributes to synaptic dysfunction. These findings provide novel information about tau-protein interactions in human brains, and they describe, for the first time, a dysfunctional consequence of tau-ribosome associations that directly alters protein synthesis.

A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5

“…The link between translational regulation and cognitive impairment is highlighted by the observation that dysregulation of the Akt-mTOR pathway that regulates translation rates is found in patients with fragile X, Down syndrome, and Rett syndrome (Troca-Marín et al, 2012). Impaired ribosomal production or assembly is also linked to the neuronal dysfunction observed in Alzheimer’s disease and other tauopathies (Meier et al, 2016). KDM5-mediated regulation of growth pathways that impact neuronal function may be evolutionarily conserved, as brain tissue of KDM5C knockout mice showed dysregulation of genes required for growth, including ribosomal protein genes (Iwase et al, 2016).…”

Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders

“…Notably, it has been shown that increased levels of pathological tau lowers protein synthesis in vitro and in vivo (Meier et al, 2016). Over-expression of P301L mutant tau in rTg4510 mice upregulates the stress kinase PERK, leading to eIF2α phosphorylation, translation inhibition, and synapse loss (Meier et al, 2015; Vanderweyde et al, 2016).…”

“…Tau also affects protein translation through direct interaction with the ribosomes and RBPs. These interactions are both altered in AD, where association with RBPs is increased (Meier et al, 2016). Tau also modulates trafficking of RNA granules, with retrograde trafficking affected more than anterograde motion (Vanderweyde et al, 2016).…”

Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?

“…This may result in a decrease in synthesis of the synaptic protein PSD-95 [81]. In addition to this direct effect of tau on protein translation, it may indirectly inhibit ribosome functions due to chronic suppression of endoplasmic reticulum-associated degradation, which in its turn activates the unfolded protein response and subsequently the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway [82].…”