• In both mouse and human motor neuron stu

    From ScienceDaily@1:317/3 to All on Thu Mar 16 22:30:28 2023
    In both mouse and human motor neuron studies, a DNA designer drug
    restored levels of a protein necessary to keep motor neurons functioning, returning activity impaired in amyotrophic lateral sclerosis; findings could lead to clinical trials.

    Date:
    March 16, 2023
    Source:
    University of California - San Diego
    Summary:
    Researchers use a DNA designer drug to restore key protein levels
    in motor neurons, delaying paralysis in a mouse model of ALS.


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    FULL STORY ==========================================================================
    In virtually all persons with amyotrophic lateral sclerosis (ALS) and in
    up to half of all cases of Alzheimer's disease (AD) and frontotemporal dementia, a protein called TDP-43 is lost from its normal location in
    the nucleus of the cell. In turn, this triggers the loss of stathmin-2,
    a protein crucial to regeneration of neurons and the maintenance of
    their connections to muscle fibers, essential to contraction and movement.


    ========================================================================== Writing in the March 16, 2023 issue of Science, a team of scientists,
    led by senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at University
    of California San Diego School of Medicine, with colleagues and elsewhere, demonstrate that stathmin-2 loss can be rescued using designer DNA drugs
    that restore normal processing of protein-encoding RNA.

    "With mouse models we engineered to misprocess their stathmin-2 encoding
    RNAs, like in these human diseases, we show that administration of one
    of these designer DNA drugs into the fluid that surrounds the brain and
    spinal cord restores normal stathmin-2 levels throughout the nervous
    system," Cleveland said.

    Cleveland is broadly credited with developing the concept of designer DNA drugs, which act to either turn on or turn off genes associated with many degenerative diseases of the aging human nervous system, including ALS,
    AD, Huntington's disease and cancer.

    Several designer DNA drugs are currently in clinical trials for
    multiple diseases. One such drug has been approved to treat a childhood neurodegenerative disease called spinal muscular atrophy.

    The new study builds upon ongoing research by Cleveland and others
    regarding the role and loss of TDP-43, a protein associated with ALS,
    AD and other neurodegenerative disorders. In ALS, TDP-43 loss impacts the
    motor neurons that innervate and trigger contraction of skeletal muscles, causing them to degenerate, eventually resulting in paralysis.

    "In almost all of instances of ALS, there is aggregation of TDP-43,
    a protein that functions in maturation of the RNA intermediates that
    encode many proteins. Reduced TDP-43 activity causes misassembly of
    the RNA-encoding stathmin-2, a protein required for maintenance of the connection of motor neurons to muscle," said Cleveland.

    "Without stathmin-2, motor neurons disconnect from muscle, driving
    paralysis that is characteristic of ALS. What we have now found is that
    we can mimic TDP- 43 function with a designer DNA drug, thereby restoring correct stathmin-2 RNA and protein level in the mammalian nervous system." Specifically, the researchers edited genes in mice to contain human STMN2
    gene sequences and then injected antisense oligonucleotides -- small
    bits of DNA or RNA that can bind to specific RNA molecules, blocking
    their ability to make a protein or changing how their final RNAs are
    assembled -- into cerebral spinal fluid. The injections corrected STMN2 pre-mRNA misprocessing and restored stathmin-2 protein expression fully independent of TDP-43 function.

    "Our findings lay the foundation for a clinical trial to delay paralysis
    in ALS by maintaining stathmin-2 protein levels in patients using our
    designer DNA drug," Cleveland said.

    Co-authors include: Michael W. Baughn, Jone Lo'pez-Erauskin, Melinda S.

    Beccari, Roy Maimon, Sonia Vazquez-Sanchez, Jonathan W. Artates and
    Eitan Acks, all at Ludwig Institute for Cancer Research-UC San Diego
    and UC San Diego; Ze'ev Melamed, Ludwig Institute for Cancer Research-UC
    San Diego, UC San Diego, and The Hebrew University of Jerusalem; Karen
    Ling, Paayman Jafar-nejad, Frank Rigo and C. Frank Bennett, all at Ionis Pharmaceuticals; Aamir Zuberi, Maximilliano Presa, Elena Gonzalo-Gil and Cathleen Lutz, all at The Jackson Laboratory; Som Chaturvedi, Mariana Bravo-Herna'ndez, Vanessa Taupin and Stephen Moore, all at UC San Diego;
    L. Sandra Ndayambaje and Ana R. Agra de Almeida Quadros, Harvard Medical School; Clotilde Lagier-Tourenne, Harvard University and Broad Institute
    of Harvard University and Massachusetts Institute of Technology.

    * RELATED_TOPICS
    o Health_&_Medicine
    # Human_Biology # Genes # Amyotrophic_Lateral_Sclerosis
    # Nervous_System
    o Mind_&_Brain
    # Huntington's_Disease # Neuroscience #
    Disorders_and_Syndromes # Alzheimer's
    * RELATED_TERMS
    o Excitotoxicity_and_cell_damage o Sensory_neuron o Mouse
    o House_mouse o DNA_microarray o Motor_neuron o DNA o
    Local_anesthetic

    ========================================================================== Story Source: Materials provided by
    University_of_California_-_San_Diego. Original written by Scott
    LaFee. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Michael W. Baughn, Ze'ev Melamed, Jone Lo'pez-Erauskin, Melinda S.

    Beccari, Karen Ling, Aamir Zuberi, Maximilliano Presa, Elena
    Gonzalo-Gil, Roy Maimon, Sonia Vazquez-Sanchez, Som Chaturvedi,
    Mariana Bravo- Herna'ndez, Vanessa Taupin, Stephen Moore,
    Jonathan W. Artates, Eitan Acks, I. Sandra Ndayambaje, Ana
    R. Agra de Almeida Quadros, Paayman Jafar-nejad, Frank Rigo,
    C. Frank Bennett, Cathleen Lutz, Clotilde Lagier-Tourenne, Don
    W. Cleveland. Mechanism of STMN2 cryptic splice- polyadenylation
    and its correction for TDP-43 proteinopathies. Science, 2023; 379
    (6637): 1140 DOI: 10.1126/science.abq5622 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2023/03/230316154104.htm

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