The role of FUS phase transition in axonal mRNA localisation and translation (360G-Wellcome-215943_Z_19_Z)

The neuropathological hallmark of the two closely related neurodegenerative diseases, ALS and FTD, is the presence of poorly soluble intracellular protein aggregates consisting of low-complexity domain-bearing RNA-binding proteins (RBPs). Intriguingly, these proteins are also key components of liquid-like ribonucleoproteins (RNPs) mediating diverse physiological processes, including transporting mRNAs to distal neurites to promote local protein synthesis (LPS). Interestingly, LPS in disease-affected neurons is often perturbed raising the possibility that the phase transition property of RBPs is critical for regulating the local supply of proteins that promote axon maintenance. Using the ALS/FTD-associated protein FUS as an example, I will investigate the effects of liquid-liquid phase separation and liquid-to-solid phase transition on axonal mRNA localisation, LPS and axon maintenance. Xenopus retinal neurons and mouse cortical neurons will be used as complementary models, in combination with optogenetic tools to achieve precise spatiotemporal control of localised FUS phase transition. A major goal is to understand the mechanisms by which aberrant intra-axonal phase transition of FUS leads to impaired LPS and axon degeneration. As effective treatments for ALS/FTD are currently unavailable, identifying differential mRNA interactors of physiological and pathological FUS and determining their translational status in axons may provide insights for clinical therapeutic options for ALS/FTD.