The Evolution of Phase-Separated TDP-43 in Stress

In this issue of Neuron, Gasset-Rosa et al. (2019) Gasset-Rosa F. Lu S. Yu H. Chen C. Melamed Z. Guo L. Shorter J. Da Cruz S. Cleveland D.W. Cytoplasmic TDP-43 de-mixing independent of stress granules drives inhibition of nuclear import, loss of nuclear TDP-43, and cell death. Neuron. 2019; 102 ( this issue) : 339-357 Google Scholar and Mann et al. (2019) Mann J.R. Gleixner A.M. Mauna J.C. Gomes E. DeChellis-Marks M.R. Needham P.G. Copley K.E. Hurtle B. Portz B. Pyles N.J. et al. RNA binding antagonizes neurotoxic phase transitions of TDP-43. Neuron. 2019; 102 ( this issue) : 321-338 Google Scholar demonstrate that cytoplasmic inclusions containing aggregated phosphorylated TDP-43 can evolve through three pathways: direct aggregation or phase-separated intermediates involving ejection from stress granules or seeding with exogenous fibrils. Interestingly, seeding with exogenous fibrils also induces cytoplasmic aggregates of nuclear pore proteins