the human tau is a microtubule-associated intrinsically unstructured protein that forms intraneuronal cytotoxic deposits in neurodegenerative diseases, like tauopathies. Recent studies indicate that in Alzheimer's disease, ribosomal dysfunction might be a crucial event in the disease pathology. our earlier studies had demonstrated that amorphous protein aggregation in the presence of ribosome can lead to sequestration of the ribosomal components. The present study aims at determining the effect of incubation of the full-length tau protein (Ht40) and its microtubule binding 4-repeat domain (K18) on the eukaryotic ribosome. our in vitro studies show that incubation of Ht40 and the K18 tau variants with isolated non-translating yeast ribosome can induce a loss of ribosome physical integrity resulting in formation of tau-rRnA-ribosomal protein aggregates. incubation with the tau protein variants also led to a disappearance of the peak indicating the ribosome profile of the HeLa cell lysate and suppression of translation in the human in vitro translation system. the incubation of tau protein with the ribosomal RNA leads to the formation of tau-rRNA aggregates. The effect of K18 on the yeast ribosome can be mitigated in the presence of cellular polyanions like heparin and tRnA, thereby indicating the electrostatic nature of the aggregation process.

Ribosome hibernation is a prominent cellular strategy to modulate protein synthesis during starvation and the stationary phase of bacterial cell growth. Translational suppression involves the formation of either factor‐bound inactive 70S monomers or dimeric 100S hibernating ribosomal complexes, the biological significance of which is poorly understood. Here, we demonstrate that the Escherichia coli 70S ribosome associated with stationary phase factors hibernation promoting factor or protein Y or ribosome‐associated inhibitor A and the 100S ribosome isolated from both Gram‐negative and Gram‐positive bacteria are resistant to unfolded protein‐mediated subunit dissociation and subsequent degradation by cellular ribonucleases. Considering that the increase in cellular stress is accompanied by accumulation of unfolded proteins, such resistance of hibernating ribosomes towards dissociation might contribute to their maintenance during the stationary phase. Analysis of existing structures provided clues on the mechanism of inhibition of the unfolded protein‐mediated disassembly in case of hibernating factor‐bound ribosome. Further, the factor‐bound 70S and 100S ribosomes can suppress protein aggregation and assist in protein folding. The chaperoning activity of these ribosomes is the first evidence of a potential biological activity of the hibernating ribosome that might be crucial for cell survival under stress conditions.

Alzheimer's disease (AD) is characterized by the appearance of neurofibrillary tangles comprising of the Tau protein and aggregation of amyloid‐β peptides (Aβ 1–40 and Aβ 1–42). A concomitant loss of the ribosomal population is also observed in AD‐affected neurons. Our studies demonstrate that, similarly to Tau protein aggregation, in vitro aggregation of Aβ peptides in the vicinity of the yeast 80S ribosome can induce co‐aggregation of ribosomal components. The RNA‐stimulated aggregation of Aβ peptides and the Tau‐K18 variant is dependent on the RNA:protein stoichiometric ratio. A similar effect of stoichiometry is also observed on the ribosome–protein co‐aggregation process. Polyphenolic inhibitors of amyloid aggregation, such as rosmarinic acid and myricetin, inhibit RNA‐stimulated Aβ and Tau‐K18 aggregation and can mitigate the co‐aggregation of ribosomal components.

Background: Alzheimer’s disease (AD) is characterized by the aggregation of Tau protein and Amyloid-β peptides (Aβ 1-40 and Aβ 1-42). A loss of ribosomal population is also observed in the neurons in affected regions of AD. Our studies had demonstrated that in vitro aggregation of amyloid forming proteins, Aβ peptides and Tau protein variants (AFPs), in the vicinity of yeast 80S ribosome can induce co-aggregation of ribosomal components. Objective: In this study the ability of minute quantities of AFP-ribosome co-aggregates to seed the aggregation of a large excess of untreated 80S ribosomes was explored. Methods: The AFPs were purified using ion-exchange chromatography. Seeded aggregation of ribosomes in the presence of minute quantities of ribosome-protein co-aggregates or ribosomal components was studied using agarose gel electrophoretic and SDS-PAGE analysis of the pellets and Sucrose Density Gradient centrifugation of the supernatant obtained after centrifugation of the aggregation reaction mixture. Results: Our studies therefore demonstrate that minute quantities of AFP-80S co-aggregate have significant seeding potential and could lead to aggregation of a large excess of fresh 80S ribosomes and this seeding ability is sustained over multiple cycles of ribosome aggregation. The aggregation propensity of ribosomal components alone could contribute towards seeding of ribosome aggregation. Conclusions: The ability of minute quantities of AFP-80S co-aggregates to seed the aggregation of large excess of fresh 80S ribosomes would result in the loss of global ribosomal population in Alzheimer’s disease afflicted neurons. Hence, subject to further validation by in vivo studies, our in vitro studies indicate at a significant mode of toxicity of amyloid aggregates that might be important in Alzheimer’s disease pathology.