{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T05:24:32Z","timestamp":1761110672367,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DA046258"],"award-info":[{"award-number":["DA046258"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Coronavirus disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a \u201ccytokine storm\u201d, and neuroinflammation. COVID-19\u2019s upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson\u2019s disease (PD), which is characterized by the formation of Lewy bodies made primarily of the \u03b1-synuclein protein encoded by the synuclein alpha (SNCA) gene. We hypothesize that COVID-19 may modulate PD progression through neuroinflammation induced by cytokine storms. This study aimed to elucidate the possible mechanisms and signaling pathways involved in COVID-19-triggered pathology associated with neurodegenerative diseases like PD. This study presents the analysis of the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN\u2019s Ingenuity Pathway Analysis (IPA), the study identified the NISP as a top-five canonical pathway\/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation.<\/jats:p>","DOI":"10.3390\/ijms241713554","type":"journal-article","created":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T08:19:39Z","timestamp":1693556379000},"page":"13554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Meta-Analysis of the Mechanisms Underlying COVID-19 Modulation of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4646-4938","authenticated-orcid":false,"given":"Jonathan","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of NeuroImmune Pharmacology, South Orange, NJ 07079, USA"},{"name":"Department of Biological Sciences, Seton Hall University, South Orange, NJ 07079, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammed","family":"Bishir","sequence":"additional","affiliation":[{"name":"Institute of NeuroImmune Pharmacology, South Orange, NJ 07079, USA"},{"name":"Department of Biological Sciences, Seton Hall University, South Orange, NJ 07079, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharman","family":"Barbhuiya","sequence":"additional","affiliation":[{"name":"Institute of NeuroImmune Pharmacology, South Orange, NJ 07079, USA"},{"name":"Department of Biological Sciences, Seton Hall University, South Orange, NJ 07079, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3865-4280","authenticated-orcid":false,"given":"Sulie L.","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of NeuroImmune Pharmacology, South Orange, NJ 07079, USA"},{"name":"Department of Biological Sciences, Seton Hall University, South Orange, NJ 07079, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"key":"ref_1","first-page":"26","article-title":"Neuro-COVID-19: A Meta-Analysis of COVID-19-Induced Neuroinflammation and Its Implications","volume":"1","author":"Sulie","year":"2020","journal-title":"Sci. Doc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s12974-018-1163-z","article-title":"Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model","volume":"15","author":"Huang","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.1093\/brain\/awac151","article-title":"Neurovascular injury with complement activation and inflammation in COVID-19","volume":"145","author":"Lee","year":"2022","journal-title":"Brain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"612","DOI":"10.3389\/fnins.2018.00612","article-title":"Parkinson\u2019s Disease: Biomarkers, Treatment, and Risk Factors","volume":"12","author":"Emamzadeh","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1007\/s12264-017-0183-5","article-title":"Biomarkers for Parkinson\u2019s Disease: Recent Advancement","volume":"33","author":"Lotankar","year":"2017","journal-title":"Neurosci. Bull."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0022-510X(97)00100-7","article-title":"Correlation between neuromorphometry in the substantia nigra and clinical features in Parkinson\u2019s disease using disector counts","volume":"151","author":"Ma","year":"1997","journal-title":"J. Neurol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3389\/fneur.2018.00455","article-title":"On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson\u2019s Disease","volume":"9","author":"Trudeau","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Stoker, T.B., and Greenland, J.C. (2018). Parkinson\u2019s Disease: Pathogenesis and Clinical Aspects, Codon Publications.","DOI":"10.15586\/codonpublications.parkinsonsdisease.2018"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41531-021-00273-9","article-title":"Lewy body disease or diseases with Lewy bodies?","volume":"8","author":"Colosimo","year":"2022","journal-title":"NPJ Park. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00401-012-1004-6","article-title":"Protein degradation pathways in Parkinson\u2019s disease: Curse or blessing","volume":"124","author":"Wahlster","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0006-8993(01)02681-6","article-title":"Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum","volume":"909","author":"He","year":"2001","journal-title":"Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1021\/acschemneuro.1c00666","article-title":"Interactions between SARS-CoV-2 N-Protein and alpha-Synuclein Accelerate Amyloid Formation","volume":"13","author":"Semerdzhiev","year":"2022","journal-title":"ACS Chem. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"117331","DOI":"10.1016\/j.jns.2021.117331","article-title":"Parkinson\u2019s disease after COVID-19","volume":"422","author":"Makhoul","year":"2021","journal-title":"J. Neurol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1002\/mds.28104","article-title":"Outcome of Parkinson\u2019s Disease Patients Affected by COVID-19","volume":"35","author":"Antonini","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"106","DOI":"10.4103\/abr.abr_350_21","article-title":"Does CetOVID-19 Escalate Aging Process? A Possible Concern","volume":"11","author":"Tayeri","year":"2022","journal-title":"Adv. Biomed. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/iid3.387","article-title":"Does COVID-19 contribute to development of neurological disease?","volume":"9","author":"Mahalakshmi","year":"2021","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/bs.irn.2022.04.004","article-title":"COVID-19 and Parkinson\u2019s disease: Acute clinical implications, long-COVID and post-COVID-19 parkinsonism","volume":"165","author":"Leta","year":"2022","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_18","first-page":"1365","article-title":"The Effect of the COVID-19 Pandemic on People with Parkinson\u2019s Disease","volume":"10","author":"Brown","year":"2020","journal-title":"J. Park. Dis."},{"key":"ref_19","first-page":"431","article-title":"Parkinson\u2019s Disease and the COVID-19 Pandemic","volume":"11","author":"Fearon","year":"2021","journal-title":"J. Park. Dis."},{"key":"ref_20","first-page":"1447","article-title":"Commentary on \u201cRepeated ethanol exposure and withdrawal alters angiotensin-converting enzyme 2 expression in discrete brain regions: Implications for SARS-CoV-2 neuroinvasion\u201d","volume":"47","author":"Chang","year":"2023","journal-title":"Alcohol: Clin. Exp. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tang, D., Comish, P., and Kang, R. (2020). The hallmarks of COVID-19 disease. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008536"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Klein, R., Soung, A., Sissoko, C., Nordvig, A., Canoll, P., Mariani, M., Jiang, X., Bricker, T., Goldman, J., and Rosoklija, G. (2021). COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis. Res. Sq., preprint.","DOI":"10.21203\/rs.3.rs-1031824\/v1"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"D\u2019Ardes, D., Boccatonda, A., Rossi, I., Guagnano, M.T., Santilli, F., Cipollone, F., and Bucci, M. (2020). COVID-19 and RAS: Unravelling an Unclear Relationship. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21083003"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"147032031666675","DOI":"10.1177\/1470320316666750","article-title":"Renin\u2013angiotensin system gene expression and neurodegenerative diseases","volume":"17","author":"Goldstein","year":"2016","journal-title":"J. Renin-Angiotensin-Aldosterone Syst."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1002\/glia.21035","article-title":"Morphine induces the release of CCL5 from astrocytes: Potential neuroprotective mechanism against the HIV protein gp120","volume":"58","author":"Avdoshina","year":"2010","journal-title":"Glia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.bbi.2013.08.006","article-title":"CCL5 and cytokine expression in the rat brain: Differential modulation by chronic morphine and morphine withdrawal","volume":"34","author":"Campbell","year":"2013","journal-title":"Brain Behav. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neuropharm.2015.01.009","article-title":"Pharmacological induction of CCL5 in vivo prevents gp120-mediated neuronal injury","volume":"92","author":"Campbell","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s12031-014-0273-z","article-title":"PACAP27 is Protective Against Tat-Induced Neurotoxicity","volume":"54","author":"Rozzi","year":"2014","journal-title":"J. Mol. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6413","DOI":"10.1523\/JNEUROSCI.20-17-06413.2000","article-title":"Selective Activation of mGlu4 Metabotropic Glutamate Receptors Is Protective against Excitotoxic Neuronal Death","volume":"20","author":"Bruno","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/sj.bjp.0706909","article-title":"RANTES stimulates Ca2+ mobilization and inositol trisphosphate (IP3) formation in cells transfected with G protein-coupled receptor 75","volume":"149","author":"Ignatov","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.brainres.2013.04.022","article-title":"RANTES has a potential to play a neuroprotective role in an autocrine\/paracrine manner after ischemic stroke","volume":"1517","author":"Tokami","year":"2013","journal-title":"Brain Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5167","DOI":"10.1007\/s12035-020-02087-x","article-title":"The Role of Brain Cyclooxygenase-2 (Cox-2) Beyond Neuroinflammation: Neuronal Homeostasis in Memory and Anxiety","volume":"57","author":"Ballaz","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_34","first-page":"236094","article-title":"Alcohol Modulation of Amyloid Precursor Protein in Alzheimer\u2019s Disease","volume":"9","author":"Masi","year":"2020","journal-title":"J. Drug Alcohol Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/acer.14978","article-title":"Commentary on \u201cAlcohol use disorder as a potential risk factor for COVID-19 severity: A narrative review\u201d","volume":"47","author":"Chang","year":"2022","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Alabed, S., Zhou, H., Sariyer, I.K., and Chang, S.L. (2021). Meta-Analysis of Methamphetamine Modulation on Amyloid Precursor Protein through HMGB1 in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094781"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13554\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:44:22Z","timestamp":1760129062000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13554"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,31]]},"references-count":36,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241713554"],"URL":"https:\/\/doi.org\/10.3390\/ijms241713554","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,8,31]]}}}