Academic literature on the topic 'Synaptonuclear messenger'

Synapses and nuclei are connected by bidirectional communication mechanisms that enable information transfer encoded by macromolecules. Here, we identified RNF10 as a novel synaptonuclear protein messenger. RNF10 is activated by calcium signals at the postsynaptic compartment and elicits discrete changes at the transcriptional level. RNF10 is enriched at the excitatory synapse where it associates with the GluN2A subunit of NMDA receptors (NMDARs). Activation of synaptic GluN2A-containing NMDARs and induction of long term potentiation (LTP) lead to the translocation of RNF10 from dendritic segments and dendritic spines to the nucleus. In particular, we provide evidence for importin-dependent long-distance transport from synapto-dendritic compartments to the nucleus. Notably, RNF10 silencing prevents the maintenance of LTP as well as LTP-dependent structural modifications of dendritic spines.

Ring Finger Protein 10 (RNF10) è una proteina messaggero sinaptonucleare localizzata a livello delle sinapsi eccitatorie e associata con la subunità GluN2A del recettore NMDA. Stimolazione dei recettori NMDA contenenti la subunità GluN2A induce il trasporto di RNF10 dalla sinapsi al nucleo e la conseguente espressione di specifici geni bersaglio, alcuni dei quali svolgono un ruolo nella patogenesi della malattia di Alzheimer o nella modulazione della morfologia delle spine dendritiche. E’ inoltre importante osservare come l’espressione di RNF10 sia ridotta negli ippocampi di pazienti con malattia di Alzheimer e come oligomeri di Aβ siano in grado di indurre il trasporto di RNF10 dalla sinapsi al nucleo. Il principale obiettivo del progetto di dottorato è la caratterizzazione del ruolo di RNF10 nei processi cognitivi e la plasticità sinaptica utilizzando gli animali RNF10 KO quale modello sperimentale. I topi RNF10 KO sono caratterizzati da una riduzione del peso corporeo e da un concomitante aumento dell’assunzione di cibo in assenza di modificazioni significative dei livelli di glucosio, insulina e FGF-21. L’analisi molecolare ha mostrato una riduzione nell’animale RNF10 delle proteine coinvolte nel metabolismo di APP nell’ippocampo e una conseguente riduzione dei livelli di Aβ. L’analisi morfologica ha mostrato un aumento significativo delle spine dendritiche mushroom e una concomitante riduzione delle spine sottili. Una approfondita analisi del comportamento ha rilevato come gli animali RNF10 KO non presentino modificazioni del comportamento motorio, sia in animali adulti che anziani, mentre è stata osservata una moderata alterata alterazione sia dell’esplorazione che della memoria a lungo termine. Inoltre, gli animali RNF10 sono caratterizzati dalla completa assenza di potenziamento a lungo termine nell’area CA1 dell’ippocampo. In conclusione, questi risultati suggeriscono il coinvolgimento di RNF10 nella patogenesi della malattia di Alzheimer e indicano un possibile ruolo di questa proteina nelle alterazioni delle capacità cognitive associate all’invecchiamento.
RING Finger Protein 10 (RNF10) is a novel synapse-to-nucleus protein messenger, enriched at the excitatory synapses and associated with the GluN2A subunit of NMDA receptors. RNF10 translocates from synapses to the nucleus, upon the activation of synaptic GluN2A-containing NMDA receptors, inducing the expression of specific target genes that have a role in Alzheimer’s disease (AD) pathogenesis or that are associated with the regulation of dendritic spine morphology. Notably, RNF10 expression is reduced in AD patients' hippocampi at the earlier stages of the disease and Aβ oligomers trigger RNF10 translocation from the synapse to the nucleus. The main objective of the PhD project is to characterize the role of RNF10 in cognitive function and synaptic plasticity, using the RNF10 KO mice as an experimental model. RNF10 KO mice present reduced body weight with an increase in food intake, and no alterations in glucose, insulin or FGF-21 levels. The molecular characterization shows downregulation of the amyloid cascade players in the hippocampus, and a consequent decrease in amyloid levels. Concerning morphological analysis, RNF10 KO animals show a significant increase in mushroom-type dendritic spines and a decrease in thin-type spines. In the behavioral characterization, both adult and aged KO animals have normal locomotion, but displayed slightly altered exploratory behavior, as well as an impaired long-term memory function. Moreover, RNF10 KO animals present a complete loss of long-term potentiation in CA1 area of the hippocampus. Overall, these data suggest an involvement of RNF10 in AD pathogenesis, pointing towards a possible role for RNF10 in cognitive dysfunction along aging.

An active synapse-to-nucleus communication is essential for long-term changes in neurons, like the regulation of neuronal plasticity and shaping neuronal morphology. Next to the fast electrochemical signaling, neurons employ a slower mechanism that involves a recently discovered class of proteins, the synaptonuclear messengers. Different studies showed the pivotal role of synaptonuclear messengers in the modulation of synaptic transmission at excitatory synapses. On the other hand, alterations of synaptonuclear messengers’ activity have been correlated to synaptic failure as observed in different synaptopathies, including both neurodevelopmental disorders and neurodegenerative diseases. Ring Finger Protein 10 (RNF10) has been recently identified as a novel synapse-to-nucleus signaling protein that specifically links the activation of synaptic GluN2A-containing NMDA receptors (NMDARs) to gene expression. RNF10 synaptonuclear trafficking is responsible for the remodeling of dendritic spines that substance the postsynaptic modifications required for long-term potentiation (LTP). However, the molecular mechanisms leading to NMDAR/RNF10 complex disruption and for initiating the importin-mediated trafficking of RNF10 to the nucleus remain unclear. In this PhD project we investigated the molecular mechanisms that underlie RNF10 activation and in this matter we discovered a protein kinase C (PKC)-dependent phosphorylation event on RNF10-Ser31, which drives RNF10 synaptonuclear trafficking. Moreover, we show that pSer31-RNF10 plays a role both in synaptonuclear signaling and in neuronal morphology. In particular, the prevention of Ser31 RNF10 phosphorylation induces a decrease in spine density, neuronal branching, and CREB signaling, while opposite effects are obtained by mimicking a stable RNF10 phosphorylation at Ser31.Based on these results, we investigated the role of RNF10 in vivo, in the RNF10-/- mouse model. In particular we studied the putative involvement of the synaptonuclear protein in neurodevelopment, focusing our attention on the first three weeks of postnatal life, which represents the critical period for neuronal differentiation and synaptogenesis in rodents. We found that RNF10-/- mice have an alteration in brain morphology, in particular in the hippocampal area, and impaired cognition. At a microscopic level, RNF10-/- deficiency alters the molecular composition and the morphology of the glutamatergic synapse. In the CA1 region of the Hippocampus, dendritic arborization of RNF10-/- neurons is severely reduced and LTP induction is compromised. Overall, these results add novel information about the functional and structural role of synaptonuclear protein messengers in shaping dendritic architecture and regulating synaptic plasticity in hippocampal neurons.