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    Home > Active Ingredient News > Antitumor Therapy > Sci Adv: The "three brothers" of Parkinson's disease, cancer, and type 2 diabetes are originally in the same line

    Sci Adv: The "three brothers" of Parkinson's disease, cancer, and type 2 diabetes are originally in the same line

    • Last Update: 2021-04-17
    • Source: Internet
    • Author: User
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    When the cell is under pressure, a chemical alarm will sound, which initiates a series of activities to protect the core part of the cell.
    At its peak, a protein called Parkin is eager to protect mitochondria, which are power plants that generate energy for cells.
    Recently,
    Salk researchers discovered a direct connection between the main sensors of cellular stress and Parkin itself.
    The same approach is also related to type
    2 diabetes and cancer, which may open up a new way to treat these three diseases.

    Salk researchers found a direct connection between the main sensors of cellular stress and Parkin itself.
    The same approach is also related to type
    2 diabetes and cancer, which may open up a new way to treat these three diseases.
    Salk researchers found a direct connection between the main sensors of cellular stress and Parkin itself.
    The same approach is also related to type
    2 diabetes and cancer, which may open up a new way to treat these three diseases.
    diabetes

    Professor Reuben Shaw, director of the Salk Cancer Center designated by NCI and senior author of the new study, said: "Our discovery represents the earliest step in Parkin's alert response.
    All other known biochemical events occurred within an hour.
    We now found in some of the activities took place within five minutes, have an impact on this important step in the cell dispose of defective mitochondria in the way of many diseases.
    scientific progress "(" April 7, 2021 in the paper "
    Science in Advances ) Has a detailed introduction.

    Science Advances

    Parkin's job is to remove mitochondria that have been damaged by cellular stress so that new mitochondria can take their place.
    This process is called mitosis.
    However, Parkin is mutated in familial Parkinson's disease, making the protein unable to clear the damaged mitochondria.
    Although scientists already know that Parkin somehow senses mitochondrial stress and initiates the process of mitosis, no one knows exactly how Parkin perceives mitochondrial problems in the first place.
    Parkin somehow knew that the mitochondria migrated to mitochondria after damage, but before it reached the mitochondria, there was no known signal to Parkin.

    Shaw's laboratory is known for its work in the areas of metabolism and cancer, and it has spent years studying in depth how cells regulate the cell's more general cell cleaning and recycling process, namely autophagy.
    About ten years ago, they discovered that an enzyme called
    AMPK controls autophagy by activating an enzyme called ULK1, which is highly sensitive to a variety of cellular stresses, including mitochondrial damage.

    The AMPK enzyme controls autophagy by activating an enzyme called ULK1, which is highly sensitive to a variety of cellular stresses including mitochondrial damage.
    The AMPK enzyme controls autophagy by activating an enzyme called ULK1, which is highly sensitive to a variety of cellular stresses including mitochondrial damage.

    After the discovery, Shaw and graduate student Portia Lombardo began searching for autophagy-related proteins that are directly activated by ULK1.
    They screened about 50 different proteins and estimated that about 10% would be suitable.
    When Parkin topped the list, they were shocked.
    Biochemical pathways are usually very complex, involving up to 50 participants, each of which activates the next.
    It is surprising that only three participants (AMPK, ULK1, Parkin) initiated a process as important as mitochondrial phagocytosis, so that Shaw hardly believed it.

    In order to confirm the correctness of the research results, the research team used mass spectrometry to accurately reveal the position where ULK1 attaches the phosphate group to Parkin.
    They discovered that it landed in a new area, and other researchers recently discovered that this area is critical to Parkin's activation, but they have not known why.
    Chien-Min Hung, a postdoctoral researcher in Shaw's lab, then did precise biochemical research to prove every aspect of the timeline and outline which proteins are doing what and where.
    Shaw's now begin to explain this critical first step Parkin activated, Shaw
    push the measure which might be "warning" signal is sent to the AMPK by ULK1 Parkin, let Parkin after the first wave struck to examine mitochondrial damage, and When necessary, it triggers the destruction of mitochondria that are severely damaged and unable to restore function.

    Push Push measure which might be "warning" signal is sent to Parkin by AMPK ULK1, let Parkin after the first wave of strikes to check the damage mitochondria and triggers the destruction of those severely impaired mitochondrial function and can not be restored if necessary.
    It may be that AMPK sends a "warning" signal to Parkin through ULK1, allowing Parkin to check the mitochondria after the first wave of damage, and if necessary, trigger the destruction of those severely damaged mitochondria that cannot recover their functions.

    In this study, the researchers found that Parkin, the core ubiquitin ligase in mitosis, and the product of the PARK2 gene mutated in familial Parkinson's disease, are the substrates of ULK1.
    A recent study found a 9-residue ("ACT") domain that is important for Parkin activation.
    This study demonstrated that AMPK-dependent ULK1 rapidly phosphorylates the conserved serine 108 in the ACT domain under mitochondrial stress.
    The phosphorylation of Parkin Ser108 occurs within 5 minutes of mitochondrial damage, which is different from the activation of PINK1 and TBK1, which is observed after 30 to 60 minutes.
    P
    mutation in ULK1 arkin phosphorylation sites, or AMPK ULK1 genetic depletion or drug ULK1 inhibition, can lead to activation delay Parkin, Parkin functions as well as for detecting defective and downstream mitotic events.
    These findings reveal an unexpected first step in the mitotic cascade.

    Mutations in the phosphorylation site of ULK1 in arkin, inherited AMPK or ULK1 depletion, or drug-induced ULK1 inhibition, will cause the delay of Parkin activation, as well as defects in the detection of Parkin function and downstream mitotic events.
    These findings reveal an unexpected first step in the mitotic cascade.
    Mutations in the phosphorylation site of ULK1 in arkin, inherited AMPK or ULK1 depletion, or drug-induced ULK1 inhibition, will cause the delay of Parkin activation, as well as defects in the detection of Parkin function and downstream mitotic events.
    These findings reveal an unexpected first step in the mitotic cascade.

    At time 0, Parkin protein (green signal) and mitochondria (red signal) are located in different parts of the cell (left image), but co-localize with mitochondria after 60 minutes (right image)

    At time 0, Parkin protein (green signal) and mitochondria (red signal) are located in different parts of the cell (left image), but co-localize with mitochondria after 60 minutes (right image)

    Maximum Parkin activity depends on the Parkin phosphorylation of ULK1

    Maximum Parkin activity depends on the Parkin phosphorylation of ULK1

    These findings have broad implications.
    AMPK is the core sensor of cell metabolism.
    It itself is activated by a tumor suppressor protein called LKB1, and LKB1 is related to a variety of cancers.
    Shaw has determined in previous work that it will also be activated by a kind of
    metformin.
    Activation of type 2 diabetes drugs.
    At the same time, a large number of studies have shown that diabetes patients taking metformin have a lower risk of cancer and aging complications.
    In fact, metformin is currently being used in clinical trials as one of the earliest "anti-aging" therapies.

    AMPK is the core sensor of cell metabolism.
    It itself is activated by a tumor suppressor protein called LKB1, and LKB1 is related to a variety of cancers.
    Shaw has determined in previous work that it will also be activated by a kind of
    metformin.
    Activation of type 2 diabetes drugs.
    AMPK is the core sensor of cell metabolism.
    It itself is activated by a tumor suppressor protein called LKB1, and LKB1 is related to a variety of cancers.
    Shaw has determined in previous work that it will also be activated by a kind of
    metformin.
    Activation of type 2 diabetes drugs.
    Metformin

    Shaw, chairman of William R.
    Brody, said: “The biggest gain for me is that
    changes in metabolism and mitochondrial health are critical in cancer, diabetes, and neurodegenerative diseases.
    Our findings indicate that we have previously shown The diabetes drugs that activate AMPK can inhibit cancer and may also help restore the function of patients with neurodegenerative diseases.
    This is because the general mechanisms that support cell health in our bodies are more integrated than anyone can imagine
    .
    "

    Changes in metabolism and mitochondrial health are critical in cancer, diabetes, and neurodegenerative diseases.
    Our findings indicate that our previously shown diabetes drugs that activate AMPK can inhibit cancer and may also help restore function in patients with neurodegenerative diseases.
    This is because the general mechanisms that support cell health in our bodies are more integrated than anyone can imagine
    .
    Changes in metabolism and mitochondrial health are crucial in cancer, diabetes, and neurodegenerative diseases.
    Our findings indicate that our previously shown diabetes drugs that activate AMPK can inhibit cancer and may also help restore function in patients with neurodegenerative diseases.
    This is because the general mechanisms that support cell health in our bodies are more integrated than anyone can imagine
    .

    Original source:

    AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy .
    Science Advances: 7 (15).
    DOI: 10.
    1126/sciadv.
    abg4544

    AMPK / ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy

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