Fig. 1.

Model of RNA granule dynamics in neurodegenerative disorders. a RNA-binding proteins associate with RNAs to form mRNPs, which assemble into large, diverse multi-mRNP complexes like tRNPs, stress granules, or processing bodies. tRNP granules determine the cytoplasmic localization and fate of the mRNA and keep the mRNA in a translationally dormant state. tRNP granules can associate and exchange mRNPs with stress granules and processing bodies in response to cellular cues such as stress. mRNAs are protected within stress granules during times of stress and serve as sites of mRNA triage where mRNP complexes are monitored for integrity and composition and are then routed to sites of reinitiation, degradation or storage. Once the stress has been removed, stress granules disassemble, mRNAs are repacked into translationally competent mRNAs and proteins are synthesized or are selectively exported to associated processing bodies for degradation. Processing bodies are sites of mRNA degradation, mRNA surveillance, translational repression, RNA-mediated silencing, and may also be involved in storage of select RNAs and recycling/modification of decay factors. Processing bodies can associate with tRNPs, stress granules, and translation machinery. Throughout the different exchanges between mRNP:RNA granules and mRNP:translation machinery, RNA-binding proteins are associated with their target mRNAs. Following translation, mRNPs can assemble back into translationally repressed tRNP granules, degraded or assembled into processing bodies. For a functioning neuron, these dynamic exchanges are important factors in the quality control of local translation at synapses and the maintenance of synaptic communication and plasticity. b Depicted is a model of how ALS/FTD mutations in FUS and TDP-43 affect RNA granule dynamics and the impact on translation and synaptic function. FUS-disease mutations cause an increase in number and size of both tRNP and stress granules. The impact of this may be two-fold: (1) FUS mutations which cause more spontaneous assembly of tRNP granules and increased translational activities would impact the normal processes of the neuron; and (2) FUS mutations which cause tRNP and stress granules to be more insoluble would lead to “seeding” of insoluble pathological inclusions associated with ALS and FTD. However, the insoluble nature of both tRNP and stress granules could also impact translation in a negative manner, which has yet to be determined. Additionally, FUS-disease mutations negatively impact the formation of processing bodies and solubility of stress granules, which would likely alter the normal functions and of these RNA granules. TDP-43-disease mutations on the other hand cause larger and fewer tRNP granules in the dendrites as well as larger and more stress granules to form in response to stress. The consequences of this may be very similar to what occurs with FUS mutations including reduced RNA granule exchanges, altered translational activities and increased “seeding” of insoluble protein aggregates. There have been no changes observed with processing bodies, but the insolubility of stress granules would predict a disturbance in mRNP:RNA granule exchanges. The net impact of FUS- and TDP-43-disease mutations would be altered RNA granule dynamics, leading to misregulation of mRNA and translation, which would impact synaptic function and cause neurodegeneration. (RBP RNA-binding protein, x a mutation in an RNA-binding protein, black arrows RNA granule exchanges, gray arrows RNA granule interactions with translation machinery, broken arrows altered RNA granule dynamics)