• Shining a light on protein aggregation i

    From ScienceDaily@1:317/3 to All on Tue Mar 22 22:30:44 2022
    Shining a light on protein aggregation in Parkinson's disease
    Optobiological control of a key protein may reveal the earliest stages of neurodegeneration in mice

    Date:
    March 22, 2022
    Source:
    PLOS
    Summary:
    A novel system to control protein aggregation in a model of
    Parkinson's disease may answer longstanding questions about how
    the disease begins and spreads, according to a new study. Initial
    results suggest that aggregation of the protein alpha-synuclein
    plays a critical role in disrupting neuronal homeostasis and
    triggering neurodegeneration.



    FULL STORY ==========================================================================
    A novel system to control protein aggregation in a model of Parkinson's
    disease may answer longstanding questions about how the disease begins and spreads, according to a new study published March 9 in the open-access
    journal PLOS Biology by Abid Oueslati of Laval University, Quebec,
    Canada, and colleagues.

    Initial results suggest that aggregation of the protein alpha-synuclein
    plays a critical role in disrupting neuronal homeostasis and triggering neurodegeneration.


    ========================================================================== Parkinson's disease is a neurodegenerative disorder, marked clinically by tremor, stiffness, and slowed movements, as well as a host of nonmotor symptoms. Within affected neurons, molecules of a protein called alpha- synuclein can be seen to clump together, forming characteristic aggregates called Lewy bodies. But it has been hard to answer whether alpha-synuclein aggregation contributes to disease development or progression, and
    when it may act in the toxic disease cascade, or whether instead the
    aggregates are innocent bystanders to some other malevolent process,
    or are even protective.

    These elements have been difficult to determine, in part because
    aggregation in cellular and animal models has not been controllable in
    either time or space.

    To address that problem, the authors turned to optobiology, a technique in which a protein of interest is fused to another protein that changes its conformation in response to light, allowing the behavior of the target
    protein to be manipulated selectively and reversibly. Here, the authors
    fused alpha- synuclein to a protein known as cryptochrome protein 2,
    from a mustard plant.

    They found that when light of the correct wavelength fell on the
    mustard protein, its conformational change triggered aggregation of its alpha-synuclein partner.

    The aggregates that formed were reminiscent of Lewy bodies in multiple important ways, including that they included several other key proteins
    besides alpha-synuclein found in Lewy bodies in people with Parkinson's disease, and that the alpha-synuclein in the aggregates adopted the characteristic beta- sheet conformation seen in many diseases of
    misfolded proteins. The aggregates induced dislocation of multiple
    cellular organelles, as Lewy bodies have been recently reported to do
    as well. They also induced misfolding in alpha- synuclein molecules not attached to the cryptochrome protein, mimicking the prion-like spread
    of aggregation seen with alpha-synuclein in the diseased brain and
    animal models.

    Finally, the authors delivered the genes for the
    alpha-synuclein-cryptochrome fusion protein to mice, directly into the substantia nigra, the structure in the brain that is most prominently
    affected by Parkinson's disease, and surgically placed an optic fiber
    to deliver light to the targeted cells. Light treatment led to formation
    of alpha-synuclein aggregates, neurodegeneration, disruption of calcium activity in downstream neuronal targets, and Parkinson- like motor
    deficits.

    "Our results demonstrate the potential of this optobiological system to reliably and controllably induce formation of Lewy body-like aggregations
    in model systems, in order to better understand the dynamics and timing of
    Lewy body formation and spread, and their contribution to the pathogenesis
    of Parkinson's disease," Oueslati said.

    Oueslati adds, "How do alpha-synuclein aggregates contribute to neuronal
    damage in Parkinson's disease? To help address this question, we developed
    a new optogenetic-based experimental model allowing for the induction
    and real-time monitoring of alpha-synuclein clustering in vivo."

    ========================================================================== Story Source: Materials provided by PLOS. Note: Content may be edited
    for style and length.


    ========================================================================== Journal Reference:
    1. Morgan Be'rard, Razan Sheta, Sarah Malvaut, Raquel Rodriguez-Aller,
    Maxime Teixeira, Walid Idi, Roxanne Turmel, Melanie Alpaugh,
    Marilyn Dubois, Manel Dahmene, Charleen Salesse, Je'ro^me
    Lamontagne-Proulx, Marie-Kim St-Pierre, Omid Tavassoly, Wen Luo,
    Esther Del Cid-Pellitero, Raza Qazi, Jae-Woong Jeong, Thomas
    M. Durcan, Luc Vallie`res, Marie-Eve Tremblay, Denis Soulet,
    Martin Le'vesque, Francesca Cicchetti, Edward A.

    Fon, Armen Saghatelyan, Abid Oueslati. A light-inducible protein
    clustering system for in vivo analysis of a-synuclein aggregation
    in Parkinson disease. PLOS Biology, 2022; 20 (3): e3001578 DOI:
    10.1371/ journal.pbio.3001578 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220322145738.htm

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