Functional Genomics Dissects Pathomechanisms in Tauopathies: Mitosis Failure and Unfolded Protein Response

Abstract

Background: Alzheimer’s disease (AD) is characterized by β-amyloid (Aβ) peptide-containing plaques and tau-containing neurofibrillary tangles. By intracerebral injection of Aβ₄₂, both pathologies have been combined in P301L tau mutant mice. Furthermore, in cell culture, Aβ₄₂ induces tau aggregation. While both Aβ₄₂ and mutant tau cause neuronal dysfunction, their modes of action are only vaguely understood. Methods: To determine which processes are disrupted by Aβ₄₂ and/or P301L mutant tau, we used transcriptomic and proteomic techniques followed by functional validation and analysis of human AD tissue. Results: Our transcriptomic study in the SH-SY5Y cell culture system revealed that Aβ₄₂ and P301L tau expression independently affect genes controlling the cell cycle and cell proliferation. Proteomics applied to Aβ₄₂-treated P301L tau-expressing SH-SY5Y cells and the amygdala of Aβ₄₂-injected P301L transgenic mice revealed that a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. Among the proteins identified was valosin-containing protein (VCP), a component of the quality control system during endoplasmic reticulum stress. Mutations in VCP have recently been linked to frontotemporal dementia. Conclusion: Our data support the mitosis failure hypothesis that claims that aberrant cell cycle reentry of postmitotic neurons induces apoptosis. Furthermore, our data underline a role of Aβ₄₂ in the stress response associated with protein folding.