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    Home > Biochemistry News > Biotechnology News > New target for Alzheimer's disease - MCL-1

    New target for Alzheimer's disease - MCL-1

    • Last Update: 2020-12-23
    • Source: Internet
    • Author: User
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    Mitochondrial dysfunction is a basic pathological feature of AD, as damaged neuron mitochondrial accumulation has been found in distributed and familial AD cases as well as in AD animal models.
    study has revealed that impaired mitochondrial function triggers energy stress, which promotes AD-specific amyloid protein-β (A beta) aggregation and Tau excessive phosphate.
    addition, mitochondrial biological dysfunction induced by the expression of the mitochondrial biological regulator PPC-1 alpha can lead to synaptic dysfunction and neuron degradation in AD.
    intracellular calcium imbalance induced by mitochondrial dysfunction can also lead to neuron death and has been shown to be associated with AD.
    based on these accumulated evidence, mitochondrial dysfunction has been identified as a key event leading to the onset of AD, and interventions to promote mitochondrial health may improve the neurodegenerative pathology associated with it.
    mitochondrial autophagy is an selective autophagy pathway for mitochondrial mass control, which devours damaged or depolarized mitochondrials through a double-layer membrane autophagy structure and then degrades with lysosome fusion.
    new research suggests that mitochondrial autophagy in AD is also affected, leading to the accumulation of dysfunctional mitochondrials, which in turn leads to synaptic dysfunction and cognitive decline.
    In contrast, in the AD mouse model, mitochondrial autophagy enhancement reduced A-beta plaques and Tau protein tangles in human neuron cells (Tau protein over-phosphate causes intra-neuron entanglement formation to be one of the classic features in the brains of AD patients) and improved memory damage.
    mitochondrial autophagy is regulated by a variety of receptors, including OPTN (ubiquitin-bindingtors optineurin), p62 (SQSTM1), NDP52 and NBR1, and NIX/BNIP3L, FUNDC1, AMBRA1, Bcl-2-L-13, and Prohibitin 2 (PHB2).
    these binds to LC3 family proteins to promote the elongation and closure of the phagosome, thereby devouring mitochondrials.
    Source: In a november 12 study published in the journal Nature Communications, a team of scientists from Zhejiang University School of Medicine, Harvard Medical School, and Taizhou College identified a powerful mitochondrial autophagy promoter, UMI-77, by screening 2,024 FDA-approved drugs and candidate small molecule drugs.
    UME-77 targets MCL-1, previously considered a key anti-apoptosis protein, and the study reveals that MCL-1 is also a mitochondrial autophagy subject that interacts with LC3A to promote mitochondrial autophagy.
    , the study confirmed that UMI-77-induced mitochondrial autophagy significantly improved AD pathology in app/PS1 mouse models.
    specifically, in this study, scientists used cell lines that steadily express mt-Keima and libraries containing 2,024 FDA-approved or candidate drugs to identify mitochondrial autophagy activators.
    mt-Keima, a chimt-Keima, has previously been identified as a powerful mitochondrial autophagy sensor.
    screening identified 20 activators that increased the relative level of mitochondrial autophagy by 1.5 times.
    interesting is that some Bcl-2 family inhibitors (also known as BH3 analogs), such as UME-77, have been found to trigger mitochondrial autophagy.
    UMI-77 is capable of inducing mitochondrial autophagy, rather than inducing mitochondrial damage or apoptosis (Source: Nature Communications) UMI-77 is an MCL-1 specific inhibitor first developed by a team at the University of Michigan School of Medicine, with the goal of blocking the interaction between MCL-1 and Bax/Bak to allow Bax/Bak to induce apoptosis.
    because MCL-1 is the target of UME-77, the researchers investigated whether this antiphase protein was involved in mitochondrial autophagy activation driven by UME-77.
    results showed that in HEK293T and HeLa cells, MCL-1 knock-down prevented degradation of UMIC-77-induced mitochondrial proteins Tom20 and Tim23.
    addition, the MCL-1 knock prevents UME-77 from handling the induced mt-Keima stimulation transfer.
    results show that MCL-1 is necessary for mitochondrial autophagy activation induced by UME-77.
    MCL-1 promotes mitochondrial autophagy, which is necessary for mitochondrial autophagy induced by UGI-77 (Source: Nature Communications) Further research reveals that MCL-1 is in fact a mitochondrial autophagy subject that interacts directly with LC3A through its LIR261-264 sequencing, which can be enhanced by UME-77, which in turn can be enhanced by mitochondrial autophagy.
    MCL-1 interaction with LC3A is required for UMI-77 induced mitochondrial autophagy (Source: Nature Communications) Then, using mt-Keima genetically modified mice, the researchers found that a 10 mg/kg dose of UMI-77 injection in the abdominal cavity effectively induced mitochondrial autophagy in mouse brain tissue.
    , the study also investigated the effects of mitochondrial autophagy induced by UMI-77 on disease pathology and behavioral esophageals in AD APP/PS1 mouse models.
    mice, from 4 months of life, were injected every other day with vehicle or UMI-77 (10 mg/kg) for 4 months.
    the Morris Water Labyrinth, the researchers found that the UMI-77 treatment improved learning and memory in APP/PS1 mice.
    UMI-77 can effectively reduce insoluble A-beta 1-42 levels in mice.
    addition, immunofluorescence results showed that after receiving UME-77 treatment, the size of A-beta plaques outside the cells in the hema region decreased significantly, and the activity of astrocytes was inhibited.
    UMI-77 treatment also reduced neuroinflammitis levels in APP/PS1 mice, as shown by significantly lower levels of inflammatory cytokines (TNF alpha and IL-6).
    is also noteworthy that UMI-77 significantly restores the mitochondrial morphology of neurons, consistent with the removal of damaged mitochondrials observed in APP/PS1 mice by inducing mitochondrial autophagy through UMI-77.
    results show that UMI-77 is a powerful lead compound for the treatment of AD.
    In the AD APP/PS1 mouse model, UMI-77 improved cognitive decline and amyloid pathology (Source: Nature Communications) Concluding that the results reveal that MCL-1 is a subject that can be targeted to induce mitochondrial autophagy, and that the potential of MCL-1 as a target for AD therapy intervention drugs is worth exploring further.
    , further support for induced mitochondrial autophagy is a viable strategy for treating this neurodegenerative disease. MCL-1 inhibitors in the clinical and preclinical development phase of Part
    Table 1 Source: NextPharma It is worth noting that MCL-1, as an anti-cancer target, is being evaluated in a number of clinical trials, and pharmaceutical giants such as Novartis, Amgen and AstraZenece have projects in clinical development.
    role of MCL-1 as a mitochondrial autophagy regulator could kick-start drug development in the new field of AD.
    resources: s1. Xufeng Cen et al. Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer's disease mouse model. Nature Communications(2020). [2] Fardokht Abulwerdi et al. A Novel Small-Molecule Inhibitor of Mcl-1 Blocks Pancreatic Cancer Growth In Vitro and In Vivo. Molecular Cancer Therapeutics(2014). Advances in drug treatment and research and development of Alzheimer's disease (Source: China Journal of New Drugs) Progress in research on Alzheimer's disease and its therapeutic drugs (Source: China Pharmacology Advisory) ( 5 ) Bcl-2 inhibitor BH3 simulation Advances in the treatment of malignant tumors in the blood system (Source: China Journal of New Medicines and Clinical Medicines) The Xia Hongguang team found that targeting MCL-1 protein-induced mitochondrial autophagy is expected to treat Alzheimer's disease (Source: Zhejiang University Medical College)
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