The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome

Abstract

The tau protein is central to the etiology of several neurodegenerative diseases, including Alzheimer's disease, a subset of frontotemporal dementias, progressive supranuclear palsy and dementia following traumatic brain injury, yet the proteins it interacts with have not been studied using a systematic discovery approach. Here we employed mild in vivo crosslinking, isobaric labeling, and tandem mass spectrometry to characterize molecular interactions of human tau in a neuroblastoma cell model. The study revealed a robust association of tau with the ribonucleoproteome, including major protein complexes involved in RNA processing and translation, and documented binding of tau to several heat shock proteins, the proteasome and microtubule-associated proteins. Follow-up experiments determined the relative contribution of cellular RNA to the tau interactome and mapped interactions to N-or C-terminal tau domains. We further document that expression of P301L mutant tau disrupts interactions of the C-terminal half of tau with heat shock proteins and the proteasome. The data are consistent with a model whereby a higher propensity of P301L mutant tau to aggregate may reflect a perturbation of its chaperone-assisted stabilization and proteasome-dependent degradation. Finally, using a global proteomics approach, we show that heterologous expression of a tau construct that lacks the C-terminal domain, including the microtubule binding domain, does not cause a discernible shift of the proteome except for a significant

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Proteomic interrogation of HSP90 and insights for medical research

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Tau protein- induced sequestration of the eukaryotic ribosome: Implications in neurodegenerative disease

“…Earlier immunohistochemical studies using tau specific antibody have demonstrated that, there is an association of the tau protein with both, the microtubule and the ribosome in the neuronal cells 2 . More recent studies of the human tau interactome have also revealed a robust association of the tau protein with the ribonucleoproteome and these studies have indicated at the preferential association of the full-length tau protein Ht40 to the 80S ribosome 3 . Although aggregation of the tau protein is the primary event in AD, it has also been demonstrated that the impairment of cellular translation and ribosome dysfunction, due to tau-ribosome interaction, is an early event in the disease.…”