RNA Protein Granules Modulate tau Isoform Expression and Induce Neuronal Sprouting

Abstract The neuronal microtubule-associated protein tau is expressed in different variants and changes in tau isoform composition occur during development and disease. Here, we investigate a potential role of the multivalent tau mRNA-binding proteins G3BP1 and IMP1 in regulating neuronal tau expression. We demonstrate that G3BP1 and IMP1 expression induces the formation of structures, which qualify as neuronal RNA-protein (RNP) granules and concentrate multivalent proteins and mRNA. We show that RNP granule formation leads to a >30-fold increase in the ratio of high molecular weight (HMW) to low molecular weight (LMW) tau mRNA and a ~12-fold increase in HMW to LMW tau protein. We report that RNP granule formation is associated with increased neurite formation and enhanced process growth. G3BP1 deletion constructs that do not induce granule formation are also deficient to induce neuronal sprouting or to change the expression pattern of tau. The data indicate that granule formation driven by multivalent proteins modulates tau isoform expression and suggest a morphoregulatory function of RNP granules during health and disease.