Dynamic Interaction between P-Bodies and Transport Ribonucleoprotein Particles in Dendrites of Mature Hippocampal Neurons

Abstract

The dendritic localization of mRNAs and their subsequent translation at stimulated synapses contributes to the experience-dependent remodeling of synapses and thereby to the establishment of long-term memory. Localized mRNAs are transported in a translationally silent manner to distal dendrites in specific ribonucleoprotein particles (RNPs), termed transport RNPs. A recent study suggested that processing bodies (P-bodies), which have recently been identified as sites of RNA degradation and translational control in eukaryotic cells, may participate in the translational control of dendritically localized mRNAs in Drosophila neurons. This study raised the interesting question of whether dendritic transport RNPs are distinct from P-bodies or whether those structures share significant overlap in their molecular composition in mammalian neurons. Here, we show that P-body and transport RNP markers do not colocalize and are not transported together in the same particles in dendrites of mammalian neurons. Detailed time-lapse videomicroscopy analyses reveal, however, that both P-bodies and transport RNPs can interact in a dynamic manner via docking. Docking is a frequent event involving as much as 50% of all dendritic P-bodies. Chemically induced neuronal activity results in a 60% decrease in the number of P-bodies in dendrites, suggesting that P-bodies disassemble after synaptic stimulation. Our data lend support to the exciting hypothesis that dendritically localized mRNAs might be stored in P-bodies and be released and possibly translated when synapses become activated.

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

“…Ultrastructural studies have demonstrated that the P-bodies are condensed fibrillar aggregates as observed in the yeast prion [PSI] 39,40 . In the same way as shown here in the assembly of TDP-43 functional aggregates, assembly of P-bodies is dynamic and, in neurons, is regulated by the neuronal activity 41 . These observations are reminiscent of the non-toxic ~500 kDa oligomers of amyloidogenic molecules found in a new type of pathogenesis pathway 42 .…”

mRNP granules

“…[11][12][13] Third, mRNP granules exhibit dynamic interactions with one another such as docking, fusion, or apparent maturation from one granule type to the next. Examples include P-body-stress granule docking, fusion 11,14 and apparent maturation, 11,12 P-body-neuronal transport granule docking, 15 P-granule-P-body docking 16 and nuage-P-body fusion, and apparent maturation into sponge bodies. 16,17 The simplest interpretation of such observations is that mRNPs are exchanged between different granules, though this has not been directly demonstrated, 13 and remains an important unresolved issue.…”

“…This later phenomenon also holds true for specific mRNAs, which exit stress granules and enter translation during the recovery phase. 62,63 Dendritic P-bodies also disassemble upon synaptic activation, 15 which may reflect entry of mRNAs into translation. mRNP granules could also be disassembled via mRNA decay, which is most likely relevant to P-bodies, given their enrichment for the decay machinery, the detection of mRNA decay intermediates within, and a correlative increase in P-body numbers when hard to degrade substrates are present.…”

“…Thus, mRNA decay blocks could also affect germ granules and neuronal transport granules, with which P-bodies also physically interact. 14,15 Notably, various mRNA degradative enzymes are found in mRNP granules besides P-bodies, such as Xrn1 in stress granules 11 and Drosophila/mouse spermatid nuage, 65 Dcp1/ Dcp2 in various germ granules, [66][67][68] and several Argonaute proteins with endonuclease activity in stress granules, 69 and various germ granules. [70][71][72][73] Whether mRNA degradation occurs in mRNP granules besides P-bodies remains poorly studied.…”

“…18 A signaling event often precedes the switch of localized mRNAs from repression to translation, followed by granule disassembly. 9,15,91 This topic has been well covered elsewhere, 92 thus the focus here will be on how granule formation may contribute to localization.…”