NOMIS Awardee Don Cleveland and colleagues have identified how phase separation of the RNA-binding protein TDP-43 can be regulated through RNA binding, disease-causing mutation, posttranslational modification, or chaperone activity inside cells.
The RNA binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. In this NOMIS-supported study, Cleveland and colleagues found that RNA binding-deficient TDP-43 (produced by neurodegeneration-causing mutations or posttranslational acetylation in its RNA recognition motifs) drove TDP-43 demixing into intranuclear liquid spherical shells with liquid cores. These droplets, which the authors named “anisosomes”, have shells that exhibit birefringence, thus indicating liquid crystal formation. Guided by mathematical modeling, the research team identified the primary components of the liquid core to be HSP70 family chaperones, whose adenosine triphosphate (ATP)-dependent activity maintained the liquidity of shells and cores. In vivo proteasome inhibition within neurons, to mimic aging-related reduction of proteasome activity, induced TDP-43-containing anisosomes. These structures converted to aggregates when ATP levels were reduced. Thus, acetylation, HSP70, and proteasome activities regulate TDP-43 phase separation and conversion into a gel or solid phase.
The study, “HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells,” was published in Science on Feb. 5, 2021.
Don W. Cleveland
Head of the Laboratory for Cell Biology at the Ludwig Institute for Cancer Research
Ludwig Cancer Research
Mechanisms of Gene Silencing and Liquid-Liquid De-mixing in the Nervous System
NOMIS RESEARCH PROJECT