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    Home > Active Ingredient News > Study of Nervous System > Science: A new mechanism for synhap damage in Alzheimer's disease, S-nitros cascade reactions, may be important in neuropathology

    Science: A new mechanism for synhap damage in Alzheimer's disease, S-nitros cascade reactions, may be important in neuropathology

    • Last Update: 2021-01-16
    • Source: Internet
    • Author: User
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    In the nervous system, excessive nitric oxide (NO) can produce nitrite stress response, resulting in neurodegenerative damage.
    in Alzheimer's disease (AD), the denationalization of β-amyloid peptides (A beta), excessive nerve excitation, neuroinstation, etc. can lead to no, followed by S-nitrosification.
    S-nitrosylation (S-nitrosylation for short) is a fast reversible and precisely oriented post-translation modification that refers to the co-price of NO cations (NO-plus) combined to the cysteine residue -base (S-).
    SNO is the basic mechanism of cell signaling in system development.
    -launched protein-related protein 1 (Drp1) is a bird glycoside triphosphase (GTPase), drp1 S-nitrosylation will lead to the excessive activation of Drp1, which in turn leads to mitochondrial fragmentation and lack of biological energy, which in turn leads to synapse loss, and the decrease in the number of synapses is closely related to the decline of AD cognitive ability.
    so this S-nitrosification reaction may be involved in the pathogenesis of the AD.
    the periodic protein-dependent kinase 5 (Cdk5) that has been S-nitrosylization transmits NO to Drp1 through a de nitrogenization reaction, forming nitrosylized Drp1.
    , however, the pathological series of continuous reactions, and the response participants have yet to be determined.
    correct answer to this question will help us better understand the pathogenesis of AD and develop potential AD therapy drugs.
    Professor Stuart A. Lipton of the Scripps Research Institute in the United States has long been involved in studying molecular signaling path pathps to prevent synhap damage, as well as neuron damage in normal aging and various neurodegenerative diseases.
    in a new study published in Science on December 3, 2020 under the title Noncanonical transnitrosylation network to synapse loss in Alzheimer's Disease, the laboratory studied the in vitro and in vivo models of AD, and Human AD post-mortem brain tissue reveals that enzymes with different catalytic activities with different biochemical pathways can form an S-nitrosyl cascading reaction that results in AD synapse loss: NO groups are transferred from the de-ubiquitinase Uch-L1 to Cdk5 and then to Drp1.
    this study suggests that a series of abnormal nitrogenization pathways and de nitrogenization pathways may play an important role in the pathophysiology of neurodegenerative diseases.
    Uch-L1, known as Ubiquitin-based end hydrolyzed enzyme L1, is a de-ubiquitinase, hydrolyzed ubiquitin-based end plus synthesis points, resulting in ubiquitin monosome.
    for convenience, UCH-L1's S-nitrosization, or S-Nitroization Uch-L1, is referred to simply as SNO-Uch-L1.
    biotin-switch assay is a biotin labeling method that can be used to directly detect proteins S-Nitrosylation in cells or tissues.
    first authors confirmed the presence of SNO-Uch-L1 in SH-SY5Y and HEK cell models using biotin conversion methods, and in AD mice, SNO-Uch-L1 levels increased significantly.
    mass spectrometry showed that the point mutation of Uch-L1's 152nd cysteine (C152S) significantly reduced this S-nitrosylation.
    And in Tg2576 and hAPP-J20 AD mice, as well as AD human brain tissue, SNO-Uch-L1 leads to reduced Uch-L1 enzyme activity, while over-expression of Uch-L1 improves synth function and memory performance.
    results suggest the importance of Uch-L1 activity in the pathogenesis of AD.
    1 A beta lymer induces the formation of SNO-Uch-L1, which in turn causes the absence of synapses (T. Nakamura et al., Science 2020; aaw0843) Immediately after, the authors note that in rat primary cortical neurons, over-expression of A-beta-1-42 lymers can lead to SNO-Uch-L1 formation and synaptic loss (Figure 1A-C).
    then, the question is, is the loss of synapses caused by A-beta 1-42 lymer, or by SNO-Uch-L1, or is it caused by the two? Uch-L1 was injected in the toothed back of AD mice that had expressed A-beta glomerates, and immunoglomerization results confirmed that SNO-Uch-L1 causes synapse mutilation (Figure 1D-E).
    also suggests a neuropathological relationship between synactal loss and cognitive decline in human AD.
    transfer reaction of the No group in Figure 2: from Uch-L1 to Cdk5 (SNOC for nitrocysteine, providing NO group) (T. Nakamura et al., Science 2020; aaw0843) So, what is the sequential relationship between Uch-L1, Cdk5, and Drp1? Or from whom to who to who (Figure 2A)? Previous studies have shown that NO can be transferred from SNO-Cdk5 to Drp1, but we do not know the NO transfer mechanism upstream of Cdk5, especially the SNO mechanism mediated by A-beta.
    through a series of experiments such as immunoprinting, biotin transformation methods, and relative rate comparison of SNO protein formation, the authors observed that knocking down Uch-L1 in the HEK cell model cell model significantly observed a decrease in cdk5 and Drp1, as well as the first (10 minutes) (25 minutes) of SNO-Cdk5 and SNO-Drp1 (25 minutes) Figure 2-3); In the neuron cell model SH-SY5Y, SNO-Cdk5 and SNO-Drp1 were significantly less likely to express the mutant Uch-L1, or C152S (SNO, which is shown to significantly inhibit Uch-L1) compared to the wild Uch-L1 (Figure 3A-E).
    these results illustrate the NO transfer order or SNO sequence, from Uch-L1 to Cdk5 to Drp1.
    shift reaction of the Uch-L1 to Cdk5 to Drp1 (T. Nakamura et al., Science 2020; aaw0843) The Nernst equation is an equation expression used to quantify the diffusional possibilities of an ion formed between two different systems.
    electrochemistry, the Nster equation is used to calculate the equilibrium voltage of the specified redox pair on the electrode relative to the standard potential.
    in short, the Ernst equation can be used to show changes in electrode potential when ion concentrations change.
    the author designed an energy equation and quantitatively analyzed the thermodynamic characteristics of S-nitrosylation reactions (SNOs).
    the results confirm once again the above conclusions regarding the continuous transfer of no-base groups.
    the correlation between these findings and the neuropathophysiology of human AD? Therefore, at the end of the paper, the researchers analyzed brain tissue after death in AD patients and found that the amount of SNO-UchL1 increased significantly in the advanced stage of AD disease, while the amount of SNO-Uch-L1 in the control group was extremely low (Figure 4A-B), which was similar to the previous view that the S-nitrosification reaction of Uch-L1 was abnormal only in the state of the disease. It is consistent, and the ratio of SNO-Uch-L1 to total UchL1 increases significantly, and synapse loss is more severe (Figure 4A-B), indicating an abnormal increase in SNO-Uch-L1 in the human AD brain, with (or exhibiting) synth pathological physiological significance (or characteristics) that may eventually aggravate AD.
    are also evident in AD mice (Figure 4B).
    SNO and comparison of Uch-L1 in the brains and mice of patients with 4 AD, as well as the S-nitrosylation (NO transfer) model (T. Nakamura et al., Science 2020; aaw0843) Conclusions and discussions, views and prospects In general, this study shows that, although A beta is neurotoxic, S-nitrosylation of the de-ubiquitinase Uch-L1 is neurotoxic, manifested as synhap damage, while Uch-L1 mutants (C152S) have neuroto protective effects.
    , the authors confirm the continuous transfer reaction of NO: first, A beta induces no, and S-nitrosylation occurs with Uch-L1, forming SNO-Uch-L1; The base reaction produces a new NO group and transfers it to Cdk5 to form SNO-Cdk5;
    this cascading reaction may affect AD's progress.
    research also suggests that revealing the nitrosyl reaction mechanisms of enzymes such as ubiquitin hydrolysase, kinase, and GTPase under disease conditions such as AD may be a new way of thinking to understand the pathological processes of these diseases, and that nitrogenization activity or de nitrogenization activity targeting these enzymes may be the therapeutic target of AD.
    Finally, on closer inspection, the evidence in this article is not so strong, and there are many unsolveed mysteries, but the "non-classical nitrosification reaction network" and "de-nitrosification reaction network" proposed by the researchers may open up new thinking and new directions for our future understanding of the complex pathological processes of neurodegenerative diseases, including AD.
    the logical relationship between this nitrosylated cascading reaction between these different enzymes and the classical AD pathological hypothesis (A beta, tau), or other non-classical AD pathological hypothesis? The answer is unknown.
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