Nuclear Transport Deficits in Tau-Related Neurodegenerative Diseases

Abstract

Tau is a cytosolic microtubule binding protein that is highly abundant in the axons of the central nervous system. However, alternative functions of tau also in other cellular compartments are suggested, for example, in the nucleus, where interactions of tau with specific nuclear entities such as DNA, the nucleolus, and the nuclear envelope have been reported. We would like to review the current knowledge about tau-nucleus interactions and lay out possible neurotoxic mechanisms that are based on the (pathological) interactions of tau with the nucleus.

Keywords: Alzheimer's disease; neurodegenerative diseases; nuclear pore complex; nucleocytoplasmic transport; tau protein.

Figure 1

Nuclear envelope distortion and cytoplasmic mislocalization of Nup98 in neurofibrillary tangles (NFTs) of Alzheimer's disease (AD) brain. Human AD (Braak V) and age-matched control brain sections were immunolabeled for phospho-tau (magenta; p-tau mix of anti-phospho-tau antibodies, pS199, pT205, pS262, pT231, and pS409), Nup98 (green), and Dapi (blue). In AD cortex, NFTs filled with phospho-tau show a crinkled/distorted nuclear envelope (white arrows) and Nup98 accumulation in the cytosol. In control nuclei, Nup98 is localized evenly to the nuclear membrane.

Figure 2

Schematic illustration of potential tau–nucleus interactions leading to nucleocytoplasmic transport (NCT) impairment in tau-related neurodegeneration. Under physiological conditions, cytosolic soluble tau is mainly localized to the neuronal axon to stabilize the microtubules. In stress conditions and in the context of neurodegenerative diseases like Alzheimer's disease and tauopathies, tau mislocalizes from the axon into the somatodendritic compartment where it gets in close proximity to the nucleus. Acute stress, for example, via heat shock, transiently increases the amount of intranuclear tau, either by active transport of tau through the nuclear pore complexes (NPC) or other unknown import mechanisms or by the enhanced expression and/or local translation of nuclear tau transcripts. Nuclear tau binds and stabilizes DNA during the time of insult, undertaking a DNA-protective role. Under persistent stress—as in the context of neurodegenerative diseases—the amount of hyperphosphorylated tau in the soma increases further and leads to different possible scenarios of tau-induced NCT disruption, which are accompanied with nuclear envelope abnormalities (e.g., invaginations) and result in neurotoxicity: (1) soluble and/or aggregated tau binds and thereby clogs the nuclear pore, resulting in cargo transport inhibition; (2) tau interacts with specific Nups of the NPC, leading to NPC disassembly and sequestration of Nups from the NPC into the cytosol, resulting in nuclear pore leakiness and co-aggregation of cytoplasmic Nups with tau; (3) somatodendritic tau interacts with Nups that under physiological conditions would associate with transcription factors to regulate gene expression. These interactions “distract” Nups and thereby indirectly affect gene expression.