Backup mandate Research Council: Exploring prion-like nucleation of liquid-liquid phase separation of hnRNPA2 in Amyotrophic Lateral Sclerosis

Project Details

Description

The formation of membraneless organelles (MOs) via liquid-liquid phase separation (LLPS) allows the cell to rapidly respond to environmental conditions such as the cellular stress response. This process is mediated by diverse multivalent interactions between RNA-binding proteins like hnRNPA2 and other macromolecules.
However, the misregulation of phase separation has been associated with the accumulation of pathogenic aggregates in
neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). It has been established that nucleation is essential to induce the formation of a new phase, being particularly explored in the context
of amyloid aggregation. Nonetheless, the role of nuclei has not yet been formally studied in the LLPS field. Therefore, approaching nucleation in the early kinetic trace of hnRNPA2 will provide valuable insights into the driving forces underneath its phase separation. The phase-separated species will be further studied to clarify the site in which secondary nucleation occurs, which leads to aggregate formation. The goal is to generate a model of the full kinetic path followed by hnRNPA2 and its two pathogenic mutants, identifying all the possible phase transitions. These models will shed light on the effect of mutations in both phase separation and aggregation, as well as in their prion-like propagation, explaining their contribution to incurable diseases.
AcronymOZR3822
StatusActive
Effective start/end date1/11/2131/10/22

Flemish discipline codes

  • Intracellular compartments and transport
  • Molecular and cell biology not elsewhere classified
  • Neurological and neuromuscular diseases

Keywords

  • liquid-liquid phase separation
  • Nucleation
  • protein aggregation