Objective: Given similarities in systemic responses after infection with SARS-CoV-2 to those reported after the 1918 pandemic, we investigated whether SARS-CoV-2 could elicit a similar parkinsonian syndrome. Here, we examined if prior infection with SARS-CoV-2 increased midbrain pathology in two models of experimental parkinsonism: 1) subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and 2) G2019S-LRRK2^ki/ki mice. WA-1 and omicron strains of SARS-CoV-2 were used.

Background: Parkinson’s Disease is a neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the SNpc of the midbrain, inflammation, and formation of Lewy bodies. Although its causes are multifactorial, viral infections, including influenza, have been associated with the development of parkinsonism (e.g. encephalitis lethargica associated with the 1918 Spanish flu pandemic).

Method: In 1), C57BL/6J mice expressing the human ACE2 receptor (k18-hACE2) were infected with SARS-CoV-2 to induce moderate disease. After 38 days, mice were administered a subtoxic dose of MPTP and euthanized 7 days later. In 2), k18-hACE2 mice crossed with G2019SLRRK2^ki/ki mice were infected with the same titer of virus and euthanized 30 days later. Subsequent neuroinflammation and SNpc DA neuron loss were determined using stereology.

Results: Mice infected with SARS-CoV-2 or MPTP alone showed no significant SNpc DA neuron loss. However, in mice infected with SARS-CoV-2, MPTP induced a greater loss of SNpc DA neurons as well as a significant increase in the number of activated microglia than SARS alone or MPTP alone respectively (p<0.05). In k18-hACE2XG2019S mice, SARS induced a ~20% loss of SNpc DA neurons (p<0.01), and a significant increase in the number of activated microglia (p<0.05) compared to uninfected mice. However, inoculation with a rabies vector-based vaccine rescued neurodegeneration in the MPTP model (p<0.001).

Conclusion: Our observations have important implications for long-term public health, given the number of people who have survived a SARS-CoV-2 infection, as well as for future public policy regarding infection mitigation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sars-cov-2-induced-neurodegeneration-in-oxidative-stress-and-genetic-models-of-parkinsons-disease/