SARS-CoV-2 infection exacerbates the cellular pathology of Parkinson's disease in human dopaminergic neurons and a mouse model

Bina Lee; Ha Nyeoung Choi; Young Hyun Che; Myungjun Ko; Hye Min Seong; Min Gi Jo; Seon-Hee Kim; Chieun Song; Subeen Yoon; Jiwoo Choi; Jeong Hee Kim; Minkyeong Kim; Min Young Lee; Sang Won Park; Hye Jung Kim; Seong Jae Kim; Do Sik Moon; Sun Lee; Jae-Hoon Park; Seung-Geun Yeo; Richard G Everson; Young Jin Kim; Kyung-Wook Hong; In-Soon Roh; Kwang-Soo Lyoo; Yong Jun Kim; Seung Pil Yun

doi:10.1016/j.xcrm.2024.101570

SARS-CoV-2 infection exacerbates the cellular pathology of Parkinson's disease in human dopaminergic neurons and a mouse model

Cell Rep Med. 2024 May 21;5(5):101570. doi: 10.1016/j.xcrm.2024.101570. Epub 2024 May 14.

Authors

Bina Lee¹, Ha Nyeoung Choi², Young Hyun Che³, Myungjun Ko⁴, Hye Min Seong⁵, Min Gi Jo⁶, Seon-Hee Kim¹, Chieun Song⁵, Subeen Yoon³, Jiwoo Choi³, Jeong Hee Kim³, Minkyeong Kim⁷, Min Young Lee⁸, Sang Won Park², Hye Jung Kim², Seong Jae Kim⁵, Do Sik Moon⁹, Sun Lee¹⁰, Jae-Hoon Park¹¹, Seung-Geun Yeo¹², Richard G Everson⁴, Young Jin Kim², Kyung-Wook Hong¹³, In-Soon Roh¹⁴, Kwang-Soo Lyoo¹⁵, Yong Jun Kim¹⁶, Seung Pil Yun¹⁷

Affiliations

¹ Department of Pharmacology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea.
² Department of Pharmacology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea; Department of Convergence Medical Science, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea.
³ Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pathology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
⁴ Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Ophthalmology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea.
⁶ Department of Pharmacology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea; Department of Pathology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
⁷ Department of Neurology, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea.
⁸ College of Pharmacy, Research Institute of Pharmaceutical Sciences, BK21 FOUR ERGID, Vessel-Organ Interaction Research Center (MRC), Kyungpook National University, Daegu 4156, Republic of Korea.
⁹ Department of Pulmonology and Critical Care Medicine, Chosun University Hospital, Gwangju 61453, Republic of Korea.
¹⁰ Department of Pathology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; Research Center, TissueIn, Inc., Seoul 06158, Republic of Korea.
¹¹ Department of Pathology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
¹² Department of Otorhinolaryngology - Head and Neck Surgery, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
¹³ Division of Infectious Diseases, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea.
¹⁴ Division of Foreign Animal Disease, Animal and Plant Quarantine Agency, Gimcheon-si, Gyeongsangbuk-do 39660, Republic of Korea.
¹⁵ Department of Veterinary Nursing, College of Health Sciences, Wonkwang University, Iksan 54538, Republic of Korea. Electronic address: [email protected].
¹⁶ Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pathology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; Research Center, TissueIn, Inc., Seoul 06158, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: [email protected].
¹⁷ Department of Pharmacology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea; Department of Convergence Medical Science, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea. Electronic address: [email protected].

Abstract

While an association between Parkinson's disease (PD) and viral infections has been recognized, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on PD progression remains unclear. Here, we demonstrate that SARS-CoV-2 infection heightens the risk of PD using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons and a human angiotensin-converting enzyme 2 (hACE2) transgenic (Tg) mouse model. Our findings reveal that SARS-CoV-2 infection exacerbates PD susceptibility and cellular toxicity in DA neurons pre-treated with human preformed fibrils (hPFFs). Additionally, nasally delivered SARS-CoV-2 infects DA neurons in hACE2 Tg mice, aggravating the damage initiated by hPFFs. Mice infected with SARS-CoV-2 display persisting neuroinflammation even after the virus is no longer detectable in the brain. A comprehensive analysis suggests that the inflammatory response mediated by astrocytes and microglia could contribute to increased PD susceptibility associated with SARS-CoV-2. These findings advance our understanding of the potential long-term effects of SARS-CoV-2 infection on the progression of PD.

Keywords: COVID-19 sequalae; DA neuron; PD; Parkinson’s disease; SARS-CoV-2; disease modeling; dopaminergic neuron; hACE2 transgenic mouse; neuroinflammation; neurological sequelae.

MeSH terms

Angiotensin-Converting Enzyme 2* / genetics
Angiotensin-Converting Enzyme 2* / metabolism
Animals
Astrocytes / metabolism
Astrocytes / pathology
Astrocytes / virology
Brain / pathology
Brain / virology
COVID-19* / pathology
COVID-19* / virology
Disease Models, Animal*
Dopaminergic Neurons* / metabolism
Dopaminergic Neurons* / pathology
Dopaminergic Neurons* / virology
Human Embryonic Stem Cells / metabolism
Humans
Mice
Mice, Transgenic*
Microglia / metabolism
Microglia / pathology
Microglia / virology
Parkinson Disease* / pathology
Parkinson Disease* / virology
SARS-CoV-2*

Substances

Angiotensin-Converting Enzyme 2
ACE2 protein, human