The Phases of Stress: Investigating the Effects of Nuclear Transport Receptors on Stress Granule Dynamics

Abstract

To face the growing burden of neurodegenerative disease, we must conduct basic research aimed at ultimately developing treatment options, as well as engage in discussions around the status and rights of patients to improve standards of care. Part I of this paper explores the effects of nuclear transport receptors (NTRs) on the dynamics of stress granules (SGs). SGs are thought to form through phase separation into dynamic, liquid-like droplets but can potentially aberrantly transition into insoluble, pathological protein aggregates implicated in neurodegenerative disease. SG-mediated toxicity is heavily interrelated with nucleocytoplasmic transport defects. Among the increasing connections between the pathways is the recruitment of NTRs, proteins that normally shuttle large molecules across the nuclear envelope, into SGs. A new model of nucleocytoplasmic transport posits that NTRs melt a local, transient path through the hydrogel thought to clog the nuclear pore. Based on this model, we hypothesized that NTRs can alter the dynamics of phase-separating organelles and get recruited into SGs to mediate entry of large molecules. To test this hypothesis, we measured the dynamics of SGs in NTR overexpression, optogenetic targeting, and knockout. Surprisingly, our results showed that increasing NTR partitioning into SGs decreased SG dynamics. Further exploration of the implications of this result and, more generally, the interplay between nucleocytoplasmic transport and stress response, can illuminate how these pathways malfunction in disease. Part II of this paper makes an argument against respecting advance directives, written statements specifying how a patient should be treated in the late stages of dementia, when their stipulations are in direct conflict with the current expressed wishes of the patient.