Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19

  1. Steve Reiken
  2. Haikel Dridi
  3. Leah Sittenfeld
  4. Xiaoping Liu
  5. Andrew R Marks

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Abstract

COVID-19, caused by SARS-CoV-2 involves multiple organs including cardiovascular, pulmonary and central nervous system. Understanding how SARS-CoV-2 infection afflicts diverse organ systems remains challenging 1,2 . Particularly vexing has been the problem posed by persistent organ dysfunction known as “long COVID,” which includes cognitive impairment 3 . Here we provide evidence linking SARS-CoV-2 infection to activation of TGF-ß signaling and oxidative overload. One consequence is oxidation of the ryanodine receptor/calcium (Ca 2+ ) release channels (RyR) on the endo/sarcoplasmic (ER/SR) reticuli in heart, lung and brains of patients who succumbed to COVID-19. This depletes the channels of the stabilizing subunit calstabin2 causing them to leak Ca 2+ which can promote heart failure 4,5 , pulmonary insufficiency 6 and cognitive and behavioral defects 7–9 . Ex-vivo treatment of heart, lung, and brain tissues from COVID-19 patients using a Rycal drug (ARM210) 10 prevented calstabin2 loss and fixed the channel leak. Of particular interest is that neuropathological pathways activated downstream of leaky RyR2 channels in Alzheimer’s Disease (AD) patients were activated in COVID-19 patients. Thus, leaky RyR2 Ca 2+ channels may play a role in COVID-19 pathophysiology and could be a therapeutic target for amelioration of some comorbidities associated with SARS-CoV-2 infection.

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  1. ScreenIT

    SciScore for 10.1101/2021.02.18.431811: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    To determine protein levels in tissue lysates, tissue proteins (20 μg) were separated by 4-20% SDS-PAGE and immunoblots were developed using antibodies against pSMAD3 (Abcam, 1:1000)
    antibodies against pSMAD3
    suggested: (Antibodies-Online Cat# ABIN1043888, RRID:AB_2725792)
    Immunoblots were developed using the following primary antibodies: anti-RyR2 (Affinity Bioreagents, 1:2000), anti-phospho-RyR-Ser(P)-2808
    anti-phospho-RyR-Ser(P)-2808
    suggested: None
    The DNP signal associated with RyR was determined using a specific anti-DNP antibody according to the manufacturer’s instructions (Millipore, Billerica, MA).
    anti-DNP
    suggested: None
    All immunoblots were developed and quantified using an Odyssey system (LI-COR Biosciences, Lincoln, NE) with IR-labeled anti-mouse and anti-rabbit IgG (1: 10,000 dilution) secondary antibodies.
    anti-mouse
    suggested: None
    anti-rabbit IgG
    suggested: None
    Ryanodine Binding: RyR2 were immunoprecipitated from 1.5 mg of tissue lysate using an anti-RyR2 specific antibody (25 μg) in 1.0 ml of a modified RIPA buffer overnight at 4 °C.
    anti-RyR2
    suggested: None
    Software and Algorithms
    SentencesResources
    All statistical analyses were performed with Prism 8.0.
    Prism
    suggested: (PRISM, RRID:SCR_005375)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2021.02.18.431811v1 on bioRxiv