Conference Agenda

Synaptonuclear messengers translate synaptic signaling into changes in gene transcription, thus modulating long-term functional modifications of the synapto-dendritic input. Alterations of these signalling pathways lead to synaptic failure, suggesting a contribution to synaptopathies such as Alzheimer’s Disease (AD). During AD early stages, the amyloid-β peptide (Aβ) oligomers trigger the disruption of mechanisms of neuronal plasticity, eventually resulting in synapse loss and in cognitive deficits. In this frame, the synaptonuclear messenger RING Finger Protein 10 (RNF10) operates as a mobile hub that docks NMDA receptor-derived signalosomes to nuclear target sites, regulating genes involved in spine morphology and AD pathogenesis. Here, we aimed at investigating the potential involvement of RNF10 in AD-synaptic dysfunction.

RNF10 expression and localization are altered in AD patients' hippocampi at the earlier stages of the disease. In the hippocampus of APP/PS1 mice, a mouse model of AD, we detected an upregulation of RNF10 signaling in the initial stages of the pathology. The RNF10 downregulation in the hippocampus of APP/PS1 mice before the onset of the pathology can restore cognitive function in AD mice. To investigate the RNF10-triggered neuronal pathways in AD, we exposed primary hippocampal cultures to Aβ oligomers. Aβ triggers a calcium-dependent NMDA receptor-induced RNF10 nuclear translocation. RNASeq data show that RNF10 silencing prevents the Aβ oligomers-driven changes in the expression of genes implicated in synaptic and mitochondrial function. In line with these results, RNF10 down-regulation prevents Aβ oligomers-triggered mitochondrial defects in neuronal cultures.

In conclusion, our findings suggest that RNF10 can play a key role in translating Aβ-induced signaling into synaptic and mitochondrial dysfunction, thus contributing to AD cognitive deficits.

Beta-amyloid (Abeta) oligomers are currently considered as the key culprit driving Alzheimer’s disease (AD) degeneration, in part through the initiation of an inflammatory cascade. As a matter of fact, neuroinflammation is one major pathomechanism in AD. Abeta plays a critical role in maintaining this process by activating microglia to produce soluble inflammatory mediators, including several chemokines. Peripheral monocytes are then attracted into the central nervous system (CNS), changing into blood-born microglia and participating in the attempt of removing toxic Abeta species. Eventually, the damage will spread because of the failure of these attempts.

Our work focused on the characterization of this peripheral contribution to the central inflammatory damage in AD, by characterizing the regulators of CNS invasion by peripheral monocytes. Abeta-induced chemotaxis and Abeta phagocytosis have been characterized in human monocytes, obtained both from patients and non demented subjects, offering new potential targets for therapeutics in AD.

TDP-43 proteinopathies are a group of diseases in which affected cells are characterized by an abnormal cytoplasmic deposits of the TAR DNA-binding protein of 43 kDa (TDP-43). These include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson’s disease (PD), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and inclusion body myopathy (IBM). In these diseases, TDP-43 undergoes a series of post-translational modifications (i.e. hyper phosphorylation, polyubiquitination and cleavage), resulting in abnormal TDP-43 fragmentation, localization and aggregation. TDP-43 aggregates exert toxicity by both loss and gain of function mechanisms, while their clearance is protective for cells. Soluble and aggregated TDP-43 are cleared primarily by the ubiquitin-proteasome system (UPS) and the autophagy–lysosome pathway (ALP) assisted by chaperones and co-chaperones proteins, respectively. Both UPS and ALP are impaired in TDP-43 proteinopathies, further worsening TDP-43 aggregation. Recently, it has been observed that cells can also release TDP-43 and its disease-associated species as free-proteins or incorporated into lipid bilayer-delimited particles, called extracellular vesicles (EVs). Since EVs can move through biological fluids, transport and release their content (i.e. proteins, RNAs and lipids) to other cells, we studied how and whether the impairment of cellular clearance systems may affect EVs compositions. In immortalized neuronal cells, we found that the secretion of disease-associated TDP-43 species into EVs is boosted when UPS, ALP or chaperones are impaired. Moreover, we observed that, under UPS or ALP blockage, EVs miRNAs cargo is different from that of physiologically secreted EVs. In particular, we identified commonly deregulated miRNA between UPS and ALP EVs, a number of which targets the prion disease pathway. These EVs were toxic to recipient cells.

Collectively our data suggest that EVs released in pathological condition can contribute to the spreading of TDP-43 disease via both proteins and miRNAs transport.

GRANTS: PRIN2020 nr.2020PBS5MJ