RT Journal Article
SR Electronic
T1 Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.18.431811
DO 10.1101/2021.02.18.431811
A1 Steve Reiken
A1 Haikel Dridi
A1 Leah Sittenfeld
A1 Xiaoping Liu
A1 Andrew R Marks
YR 2021
UL http://biorxiv.org/content/early/2021/02/18/2021.02.18.431811.abstract
AB 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 challenging1,2. Particularly vexing has been the problem posed by persistent organ dysfunction known as “long COVID,” which includes cognitive impairment3. 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 (Ca2+) 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 Ca2+ which can promote heart failure4,5, pulmonary insufficiency 6 and cognitive and behavioral defects7–9. 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 Ca2+ 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.Competing Interest StatementColumbia University and ARM own stock in ARMGO, Inc. a company developing compounds targeting RyR and have patents on Rycals