The Mechanism Of Activity Dependent LoNA Regulates Protein Translation

Neuronal activities are known to regulate protein synthesis via multiple mechanisms,including phosphorylation of key transcription factors,processing and maturation of both rRNAs and mRNAs,and control of the nucleolar number.Nucleolar numbers vary throughout development in neurons,suggesting that changes in the neuronal demands for protein synthesis are accommodated by regulation of nucleolar assembly.rRNA,the RNA component of the ribosome,is essential for protein synthesis in all living organisms.The stimulation of neurons increases rRNA production,and decreased rRNA synthesis and nucleolar disruption are primary signs of cellular stress associated with aging and neurodegenerative disorders.These observations suggest an essential role of nucleoli and ribosome RNA biogenesis implicated in learning and memory,as well as in neurological diseases.Protein synthesis in neuronal cell bodies is undoubtedly important.However,local protein translation is proved to be crucial in synaptic development and plasticity.A considerable number of mRNAs,including those encoding signaling molecules,scaffolds,and receptors,are transported to dendrites and synapses at appreciable levels.Moreover,spine-localized polyribosomes are substantially increased upon potentiation,indicating that there is delicate regulation of ribosome number/function to meet the demands of local protein synthesis.Evidence suggests that local translation is functionally indispensable for synaptic and behavioral plasticity.Non-coding RNAs(ncRNAs)are key regulators of translational control,and may regulate mRNAs via effects on protein translation,as well as by transcriptional and epigenetic mechanisms.The local regulation of mRNA stability and translation is crucial for synaptic plasticity and is especially amenable to regulation by ncRNAs.For example,the brain cytoplasmic ncRNA BC1/BC200 is associated with FMRP-mediated translational repression in dendrites.However,these ncRNAs are localized to dendrites and synapses,and primarily function locally.Identification of ncRNAs in neuronal soma,the primary site of translational control,will further our understanding of translational control.Here,we identify a nucleolar-specific IncRNA(LoNA),its 5' portion binds and sequesters nucleolin to suppress rRNA transcription,and its snoRNA like 3' end recruits and diminishes fibrillarin activity to reduce rRNA methylation.Activity-dependent decrease of LoNA leads to elevated rRNA and ribosome levels,an increased proportion of polysomes,mRNA polysome loading,and protein translation.In addition,transport of ribosomes to synapses is particularly promoted,resulting in increased levels of AMPA/NMDA receptor,enhanced synaptic plasticity,long-term potentiation and consolidated memory.Strikingly,hippocampal LoNA deficiency not only enhances long-term memory in WT mice,but also restores impaired memory function in APP/PS1 transgenic mice.Together,these findings reveal the multifaceted role of LoNA in modulating ribosome biogenesis to meet the translational demands of long-term memory.