Liquid–liquid phase separation studies to modulate pathogenic proteins in neurodegeneration

Liquid–liquid phase separation (LLPS) forming liquid condensates has been observed with a wide range of proteins in vitro and in vivo, and this enables effective signaling and enzymatic reactions. The aberrant liquid–solid phase transition of FUS, TDP-43 and other DNA/RNA-binding proteins leads to their accumulation as solid aggregates, broad-ranging cellular dysfunction and stress, driving the development of neurodegenerative diseases, including familial amyotrophic lateral sclerosis (ALS/MND) and frontotemporal lobar degeneration (FTLD). Together we will test and develop strategies to disrupt these pathogenic processes with applications across a broad range of neurological conditions.

We are looking for creative and conscientious students with a strong interest in biophysics, protein folding or neurodegeneration to investigate the molecular determinants of liquid-liquid-solid phase protein transitions. The training will include developing expertise in ex vivo isolation and characterization of pathogenic inclusions from tissue, tissue culture models of LLPS for functional readouts, and investigation of the environmental and genetic drivers of these transitions at the molecular level. Students will develop broad expertise in ex vivo pathology isolation and characterisation, protein expression, folding and dynamics, investigation of molecular determinants of phase transitions in low-complexity regions implicated in disease, and to develop strategies to disrupt these aberrant processes. This is an opportunity to develop broad ranging skills with discrete, focused milestones for publication.