Local RNA translation at the synapse and in disease

Abstract

Local regulation of protein synthesis in neurons has emerged as a leading research focus because of its importance in synaptic plasticity and neurological diseases. The complexity of neuronal subcellular domains and their distance from the soma demand local spatial and temporal control of protein synthesis. Synthesis of many synaptic proteins, such as GluR and PSD-95, is under local control. mRNA binding proteins (RBPs), such as FMRP, function as key regulators of local RNA translation, and the mTORC1 pathway acts as a primary signaling cascade for regulation of these proteins. Much of the regulation occurs through structures termed RNA granules, which are based on reversible aggregation of the RBPs, some of which have aggregation prone domains with sequence features similar to yeast prion proteins. Mutations in many of these RBPs are associated with neurological diseases, including FMRP in fragile X syndrome; TDP-43, FUS (fused in sarcoma), angiogenin, and ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in spinocerebellar ataxia; and SMN (survival of motor neuron protein) in spinal muscular atrophy.

Figure 1.

Translational control by RBPs. RBPs act in the nucleus, where they have been implicated in splicing and transcription. The same RBPs also exhibit important roles outside the nucleus. RBPs function to transport mRNAs to the synapse, during which they silence translation. At the synapse, RBPs function in a complex network regulating local translation. Finally, in response to stress, RBPs sequester 7mG capped mRNA in large aggregates, which allows synthesis of protective uncapped mRNA, such as heat shock proteins. Orange, RBPs that function silence translation. Magenta, RBPs that function in splicing and transport. Green, RBPs that activate RNA translation. Blue/orange striped line, Microtubules.