Neuronal functions of the two RNA-binding proteins G3BP1 and FUS in heath and disease: beyond the formation of stress granules

In response to various cellualr stress stimuli, cells will arrest protein synthesis via the formation of stress granules (SGs). Many RNA-binding proteins are present in SGs, including G3BP1 and Fused in Sarcoma (FUS). G3BP1 is the major nucleation factor during the initaition of SG formation, while aggregation of FUS in SGs is widely implicated in neurodegeneration such as amyotrophic lateral sclerosis (ALS). In this talk, I will describe the essential role of G3BP1 in the development of dendritic spines, the compartment where excitatory synapses are located, thereby indicating that the biological significance of G3BP1 extends beyond its role in stress response. I will further discuss the use of human induced pluripotent stem cells (hiPSCs) to investigate the impact of ALS-related FUS mutations in brain neurons. As ALS is primarily regarded as a a motoneuron disease, previous studies almost exclusively differentiated hiPSCs into spinal motoneurons to investigate FUS-ALS. Nonetheless, defects in the cerebral cortex and cognitive functions have been widely reported in FUS-ALS patients as well as animal models. Yet how FUS mutations affect human neurons in the brain remains largely unknown. We employ genome editing to knock-in the P525L disease mutation into the genome of hiPSCs. Upon differentiation into cortical neurons, the P525L-FUS neurons exhibit reduced dendritic arborizations and abnormality in synapse development despite the absence of FUS aggregates. Our study therefore provides new insights into the pathophysiology of ALS-FUS in human brain neurons by revealing that the mutant protein can exert detrimental effect without the need to form cytoplasmic aggregates. To study the effects of the FUS mutation in a more physiological condition, we are currently characterizing the hiPSC-derived FUS mutant neruons in vivo after transplantation into mouse brains.