TDP-43 in nuclear condensates: where, how, and why

TDP-43 is an abundant and ubiquitously expressed nuclear protein that becomes dysfunctional in a spectrum of neurodegenerative diseases. TDP-43's ability to phase separate and form/enter biomolecular condensates of varying size and composition is critical for its functionality. Despite the high density of phase-separated assemblies in the nucleus and the nuclear abundance of TDP-43, our understanding of the condensateTDP-43 relationship in this cellular compartment is only emerging. Recent studies have also suggested that misregulation of nuclear TDP-43 condensation is an early event in the neurodegenerative disease amyotrophic lateral sclerosis. This review aims to draw attention to the nuclear facet of functional and aberrant TDP-43 condensation. We will summarise the current knowledge on how TDP-43 containing nuclear condensates form and function and how their homeostasis is affected in disease.