COVID‐19 Infection Enhances Susceptibility to Oxidative Stress–Induced Parkinsonism

Abstract

Background Viral induction of neurological syndromes has been a concern since parkinsonian‐like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection with those observed after pandemic influenza, there is a question whether a similar syndrome of postencephalic parkinsonism could follow coronavirus disease 2019 infection. Objective The goal of this study was to determine whether prior infection with SARS‐CoV‐2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism. Methods K18‐hACE2 mice were infected with SARS‐CoV‐2 to induce mild‐to‐moderate disease. After 38 days of recovery, mice were administered a non‐lesion‐inducing dose of the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and euthanized 7 days later. Subsequent neuroinflammation and substantia nigra pars compacta (SNpc) dopaminergic (DA) neuron loss were determined and compared with SARS‐CoV‐2 or MPTP alone. Results K18‐hACE2 mice infected with SARS‐CoV‐2 or MPTP showed no SNpc DA neuron loss after MPTP. In mice infected and recovered from SARS‐CoV‐2 infection, MPTP induced a 23% or 19% greater loss of SNpc DA neurons than SARS‐CoV‐2 or MPTP, respectively (P < 0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in both the SNpc and striatum of the SARS‐CoV‐2 + MPTP group compared with SARS‐CoV‐2 or MPTP alone. Conclusions Our observations have important implications for long‐term public health, given the number of people who have survived SARS‐CoV‐2 infection, as well as for future public policy regarding infection mitigation. However, it will be critical to determine whether other agents known to increase risk for PD also have synergistic effects with SARS‐CoV‐2 and are abrogated by vaccination. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

SARS-CoV-2 Spike Protein in the Pathogenesis of Prion-like Diseases

“…It also induced upregulation of α-synuclein expression. They suggested that this property could be the underlying mechanism accounting for the link between COVID-19 and PD [12].…”

Investigating neurological symptoms of infectious diseases like COVID-19 leading to a deeper understanding of neurodegenerative disorders such as Parkinson's disease

“…In addition, recent research found that SARS-CoV-2 nucleocapsid protein accelerated alpha-synuclein aggregation ( in vitro ) ( 23 ), and the presence of SARS-CoV-2 existed in the substantia nigra of 6 COVID-19 patients ( 24 ). Further, SARS-CoV-2 infection caused dopaminergic neuron (derived from human pluripotent stem cells) senescence (both in vitro and in vivo ) ( 24 ), worsened preexisting PD symptoms in around 59% of PD patients ( 25 ), and increased susceptibility to parkinsonism induced by oxidative stress ( 9 ). These findings suggested that SARS-CoV-2 infection increases individual vulnerability of PD or parkinsonism, leading to the onset or progression of PD (or parkinsonism) or in some cases unmasking preexisting pre-symptomatic PD in susceptible individuals ( 26 ).…”

“…Searching for possible links between COVID-19 and PD or parkinsonism ( 9 , 26 , 27 ), clinicians and medical researchers have been asking, discussing and debating: Will there be a post-COVID-19 parkinsonism after the COVID-19 pandemic ( 11 , 26 , 28 – 31 )? There are currently 10 reported COVID-19 associated acute parkinsonism cases ( 16 – 22 ), but according to the estimated incidence of 0.11% for parkinsonism among COVID-19 survivors in the large-cohort ( n = 236,379) long follow-up study ( 1 ), 260 of them developed parkinsonism 6 months after COVID onset ( 1 ), which provided strong evidence and support for post-COVID-19 parkinsonism.…”

“…would be over 17 million by 2040 ( 32 ). The widespread SARS-CoV-2 infection during the COVID-19 pandemic increased the risk of PD or parkinsonism ( 9 , 24 , 26 ), either triggered parkinsonism ( 16 , 19 ) or unmasked preexisting prodromal (or pre-symptomatic) PD in COVID-19 patients or survivors [especially in long COVID ( 1 )] around the globe. In addition, since (1) a number of COVID-19 symptoms (loss of sense of smell, taste impairment, dizziness, etc.)…”

“…and long COVID symptoms (cognitive impairment, tremors, functional mobility impairment, gastrointestinal problems, sleep disorder, etc.) ( 13 , 33 – 35 ) overlap with symptoms of PD or parkinsonism, (2) the evidence of the COVID-associated acute parkinsonism cases ( 16 – 22 ), the 260 (0.11%) post-COVID-19 parkinsonism cases ( 1 ), high percentages of functional mobility impairment (44%) and mobility decline (20.2%) in long COVID ( 13 ), and an increasing trend of motor symptoms like tremors ( 35 ) among patients with long COVID has suggested that SARS-CoV-2 infection may trigger (acute or chronic) neural injury in the nigrostriatal system, a long lasting neuroinflammation and subsequent motor-associated neurodegeneration, (3) there are much similarities between SARS-CoV-2 and H1N1 influenza virus [in viral contagiousness/transmission, viral infection fatality/severity, immune system activation, cytokine storm induction, neuroinvasion, cellular aging pathway modulation, association with increased risk/susceptibility to PD or parkinsonism ( 9 , 15 ), etc. ], and the risk factors for the recent Parkinson's “pandemic” (such as aging and industrial/agricultural/chemical/metal pollution) still exist ( 32 ), there might be an increased global risk of PD or parkinsonism associated with long COVID and a possible post-COVID-19 parkinsonism ( 1 ).…”