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Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Despite advancements in research, no cure exists due to an incomplete understanding of the molecular effects of MeCP2 deficiency. Previous studies have identified impaired tropomyosin receptor kinase (Trk) neurotrophin (NTP) signaling and mitochondrial redox imbalances as key drivers of the pathology. Moreover, altered glycosphingolipid metabolism has been reported in RTT. GM1 ganglioside is a known regulator of the nervous system, and growing evidence indicates its importance in maintaining neuronal homeostasis via its oligosaccharide chain, coded as GM1-OS. GM1-OS directly interacts with the Trk receptors on the cell surface, triggering neurotrophic and neuroprotective pathways in neurons. In this study, we demonstrate that GM1-OS ameliorates RTT deficits in the Mecp2-null model. GM1-OS restored synaptogenesis and reduced mitochondrial oxidative stress of Mecp2-knock-out (ko) cortical neurons. When administered in vivo, GM1-OS mitigated RTT-like symptoms. Our findings indicate that GM1-OS effects were mediated by Trk receptor activation on the neuron's plasma membrane. Overall, our results highlight GM1-OS as a promising candidate for RTT treatment. [ABSTRACT FROM AUTHOR]

Perception of our environment entirely depends on the close interaction between the central and peripheral nervous system. In order to communicate each other, both systems must develop in parallel and in coordination. During development, axonal projections from the CNS as well as the PNS must extend over large distances to reach their appropriate target cells. To do so, they read and follow a series of axon guidance molecules. Interestingly, while these molecules play critical roles in guiding developing axons, they have also been shown to be critical in other major neurodevelopmental processes, such as the migration of cortical progenitors. Currently, a major hurdle for brain repair after injury or neurodegeneration is the absence of axonal regeneration in the mammalian CNS. By contrasts, PNS axons can regenerate. Many hypotheses have been put forward to explain this paradox but recent studies suggest that hacking neurodevelopmental mechanisms may be the key to promote CNS regeneration. Here we provide a seminar report written by trainees attending the second Flagship school held in Alpbach, Austria in September 2018 organized by the International Society for Neurochemistry (ISN) together with the Journal of Neurochemistry (JCN). This advanced school has brought together leaders in the fields of neurodevelopment and regeneration in order to discuss major keystones and future challenges in these respective fields. [ABSTRACT FROM AUTHOR]

Recently, we demonstrated that the GM1 oligosaccharide, II3Neu5Ac-Gg4 (OligoGM1), administered to cultured murine Neuro2a neuroblastoma cells interacts with the NGF receptor TrkA, leading to the activation of the ERK1/2 downstream pathway and to cell differentiation. To understand how the activation of the TrkA pathway is able to trigger key biochemical signaling, we performed a proteomic analysis on Neuro2a cells treated with 50 μM OligoGM1 for 24 h. Over 3000 proteins were identified. Among these, 324 proteins were exclusively expressed in OligoGM1-treated cells. Interestingly, several proteins expressed only in OligoGM1-treated cells are involved in biochemical mechanisms with a neuroprotective potential, reflecting the GM1 neuroprotective effect. In addition, we found that the exogenous administration of OligoGM1 reduced the cellular oxidative stress in Neuro2a cells and conferred protection against MPTP neurotoxicity. These results confirm and reinforce the idea that the molecular mechanisms underlying the GM1 neurotrophic and neuroprotective effects depend on its oligosaccharide chain, suggesting the activation of a positive signaling starting at plasma membrane level. [ABSTRACT FROM AUTHOR]

Recently, we highlighted that the ganglioside GM1 promotes neuroblastoma cells differentiation by activating the TrkA receptor through the formation of a TrkA–GM1 oligosaccharide complex at the cell surface. To study the TrkA–GM1 interaction, we synthesized two radioactive GM1 derivatives presenting a photoactivable nitrophenylazide group at the end of lipid moiety, 1 or at position 6 of external galactose, 2; and a radioactive oligosaccharide portion of GM1 carrying the nitrophenylazide group at position 1 of glucose, 3. The three compounds were singly administered to cultured neuroblastoma Neuro2a cells under established conditions that allow cell surface interactions. After UV activation of photoactivable compounds, the proteins were analyzed by PAGE separation. The formation of cross‐linked TrkA–GM1 derivatives complexes was identified by both radioimaging and immunoblotting. Results indicated that the administration of compounds 2 and 3, carrying the photoactivable group on the oligosaccharide, led to the formation of a radioactive TrkA complex, while the administration of compound 1 did not. This underlines that the TrkA–GM1 interaction directly involves the GM1 oligosaccharide, but not the ceramide. To better understand how GM1 relates to the TrkA, we isolated plasma membrane lipid rafts. As expected, GM1 was found in the rigid detergent‐resistant fractions, while TrkA was found as a detergent soluble fraction component. These results suggest that TrkA and GM1 belong to separate membrane domains: probably TrkA interacts by 'flopping' down its extracellular portion onto the membrane, approaching its interplay site to the oligosaccharide portion of GM1. The plasma‐membrane GM1‐TrkA interaction is an absolute milestone but the precise molecular mechanism has not been precisely defined. By the use of photoactivable GM1, we demonstrated that only GM1 having the photoactivable group at the external galactose unit crosslinks TrkA. We propose that GM1‐TrkA interaction occurs thanks to the TrkA extracellular portion, present in the fluid plasma‐membrane microenvironment, that lying on the cell surface, reaches the GM1 oligosaccharide moiety, whose ceramide is inserted within the rigid plasma‐membrane microdomain. [ABSTRACT FROM AUTHOR]