SARS-CoV-2 Infection and Alpha-Synucleinopathies: Potential Links and Underlying Mechanisms
Abstract
:1. Introduction
2. The Relationship Between COVID-19 and PD
2.1. Parkinsonism as a Consequense of COVID-19
Aim | Method/Subject of Analysis | Results | Reference |
---|---|---|---|
Meta-analysis of serum/plasma proteomic data from COVID-19 patients assaying the links between SARS-CoV-2 infection and neurological disorders, specifically AD and PD. | Mass spectrometry-based proteomics data with a total of 538 COVID-19 patients and 523 healthy controls. | Analysis confirmed a direct correlation in the expression patterns of 24 proteins implicated in AD and 23 proteins involved in PD with COVID-19. A protein–protein interaction network and cluster analysis revealed direct correlation in differential expression between COVID-19 and PD and identified SNCA as a hub protein. | [50] |
Meta-analysis answering the question: Are the new-onset neurodegenerative diseases long-term sequelae of the SARS-CoV-2 infection? | Articles published up to 10 January 2023. Twelve studies involving 33,146,809 individuals (2,688,417 post-COVID-19 cases and 30,458,392 controls). | The significant correlation between SARS-CoV-2 infection and increased risk for new-onset AD (Hazard Ratio [HR] = 1.50), dementia (HR = 1.66), and PD (HR = 1.44). | [57] |
The systematic review concentrated on the impact of post-SARS-CoV-2 immune-mediated responses/the host’s altered immune counter-offensive on the occurrence of neurodegenerative diseases like PD in a complex interrelation between genetic and epigenetic risk factors. | A synthetic and systematic literature review based on the “Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology; 104 papers were finally selected. | It is too early to establish if the neuroinflammatory events accompanied by COVID-19 could activate long-term neurodegenerative consequences and lead to new cases of PD occurrence and the worsening of the existing disease outcome. Further clinical and prospective longitudinal cohort studies are required. | [58] |
The analysis of the possible mechanisms involved in COVID-19-induced neuropathology like PD. The analysis of pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. | The analysis of the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. The molecules and chemicals associated with COVID-19 and PD were subjected to Ingenuity Pathway Analysis (IPA) “Grow”; 81 overlapping molecules between COVID-19 and PD were further subjected to IPA’s “Core Analysis” tool to identify the upstream regulators and signaling pathways. | Core Analysis revealed the neuroinflammation signaling pathway (NISP) to be one of the principal signaling pathways involved and SNCA as the top upstream controller associated with both COVID-19 and PD. A network connectivity pathway map of the downstream effects of COVID-19 revealed that ACE2 blocking upregulates SNCA expression, potentially accelerating PD progression. | [59] |
A systematic review and meta-analysis of studies reporting parkinsonism cases among patients recovering from COVID-19. | Research from seven major databases covering a timeline of 1 January 2020 to 1 January 2022. Ten studies met the inclusion criteria and covered thirteen patients with a median age of 60.0. There were eight males (61.5% of patients), and 53.8% of individuals were documented to have at least one comorbidity. Fisher’s exact test was used to examine the factors connected with COVID-19 and parkinsonism as its results. | Indication of parkinsonism as post-COVID-19 neurological sequelae. Cogwheel rigidity was the most common manifestation of parkinsonism in eleven patients. The most standard medicine modality used was Levodopa (76.9% of cases). Ten patients (76.9%) with bradykinesia achieved a complete recovery. | [60] |
2.2. The Prevalence, Outcomes, and Prognosis of COVID-19 in Patients Diagnosed with PD
2.3. The Theory of SARS-CoV-2 Neuroinvasion in PD
2.4. The Role of SARS-CoV-2 in α-Syn Alterations
2.5. Promising Therapeutic Targets for Both PD and COVID-19
3. The Connection Between COVID-19 and α-Synucleinopathies Other Than PD
3.1. DLB
3.2. MSA
3.3. PAF
3.4. RBD
4. Age and Gender Aspects of Relationships Between SARS-CoV-2 Infection and α-Synucleinopathies
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Aim | Method/Subject of Analysis | Results | Reference |
---|---|---|---|
Meta-analysis aimed to determine the prevalence of COVID-19, its symptoms in elderly patients with PD and the association between PD and COVID-19. | Twenty articles were selected from January 2019 to 20 October 2021. | The prevalence of COVID-19 and the hospitalization of patients with PD was 1.06% and 0.98%, respectively; the prevalence of depression and anxiety during the pandemic in these groups was 46% and 43%, respectively; the risk of COVID-19 infection was equal in the PD patients and healthy controls. | [69] |
Analysis of the prevalence of neurological disorders (including PD) in COVID-19 without overlapping meta-analysis errors. | Four meta-analyses involving 182,386 COVID-19 patients, published from November 2019 to September 2021. | The combined prevalence of PD during the COVID-19 pandemic was 0.67%; PD was not a statistically significant risk of mortality in COVID-19 patients (Odds Ratio [OR] = 3.94). | [70] |
Review of all qualified studies to quantify the strength of affinities between pre-existing neurodegenerative diseases, SARS-CoV-2 vulnerability, and COVID-19 outcome. | Pre-registered systematic review with frequentist and Bayesian meta-analyses; 9 January 2023 was the final search date; 136 primary studies (total sample size n = 97,643,494), reporting on 268 effect-size estimates, met the inclusion criteria. | The odds for a positive SARS-CoV-2 test result were raised for individuals with pre-existing AD (OR = 2.86), dementia (OR = 1.83), and PD (OR = 1.65). People with pre-existing AD were at a higher risk for COVID-19-related hospital admission (OR = 3.72), but people with MCI, PD, or mixed dementia were not. People with AD and PD were at a higher risk for COVID-19-related intensive care unit admissions (pooled OR range: 1.55–1.65). All neurodegenerative disorders were at a higher risk for COVID-19-related mortality (pooled OR range: 1.56–2.27). In general, people with neurodegenerative disease and MCI are at a disproportionally high risk of acquiring COVID-19 and have a poor outcome once infected. | [71] |
The assessment of the association between pre-existing neurological conditions and COVID-19 outcomes. | Literature review of systematic reviews, meta-analyses, and scoping reviews published between 1 January 2020 and 1 January 2023. Thirty-nine articles fulfilled the inclusion criteria, with data estimating >3 million people from 51 countries. | In total, 92.3% of the articles suggested a significant link between pre-existing neurological disorders including cerebrovascular disease, PD, AD and other dementias, and epilepsy and an increased risk of severe COVID-19 and mortality in the acute infectious period. | [72] |
The systematic review and meta-analysis aimed to investigate the influence of the COVID-19 pandemic on neuropsychiatric disorders (depression, anxiety, stress) and sleep disturbances (sleep quality, insomnia), as well as the quality of life among patients with PD, MS, and AD compared with healthy people. | Observational studies (i.e., cross-sectional, case–control, cohort) raised from the research of 7 databases between March 2020 and December 2022. An analysis of eighteen studies (PD = 7, MS = 11) with a total of 627 individuals with PD (healthy controls = 857) and 3923 individuals with MS (healthy controls = 2432); twelve studies (PD = 4, MS = 8) were included in the meta-analysis. | The COVID-19 pandemic negatively affected people with PD, evidenced by significantly higher levels of depression and stress, measured by standardized mean differences (SMD) = 0.40 and 0.60, respectively. MS patients also presented higher levels of depression/stress, and additionally lower quality of life compared with the healthy control groups. | [73] |
Meta-analysis of factors that affect the well-being of PD individuals from diverse populations during the pandemic. | Research of articles published between 2020 and 2022; the analysis includes twenty-seven studies involving 13,878 patients from America, Europe, Asia, and Africa. | High prevalence of diminished physical activity and exercise, and aggravating motor and neuropsychiatric symptoms (17–56%) during the COVID-19 pandemic, with patients in lower-income countries being exceptionally vulnerable, i.e., anxiety (adjusted Odds Ratios, [aOR] = 8.94), sleep (aOR = 5.16), and PD symptoms (aOR = 3.57). Younger age correlated with decreased physical activity, exercise, sleep, and worsening PD symptoms. Female PD patients reported a more pronounced decrease in physical activity and sleep disturbances. | [74] |
Systematic review and meta-analysis aimed to determine the pooled prevalence of COVID-19 in PD patients. | Thirty articles for meta-analysis with the number of included patients differed between 10 and 64,434; published before Sep 2021. | The pooled prevalence of COVID-19 infection in PD cases was 5% besides mortality and hospitalization rates were 12% and 49%, respectively. The pooled prevalence of fever and cough in cases with PD was 4% and 3%, respectively. | [75] |
Systematic review aimed to determine the impact of PD on the COVID-19 prevalence and patient prognosis. | Thirteen papers including 8649 PD patients and 88,710 control subjects/till 12 March 2021. | The pooled prevalence rate of COVID-19 among PD patients was 2.12%. The hospitalization rate for PD patients with COVID-19 was 39.89%, while the total mortality rate was 25.1%. There were no significant differences in hospitalization and mortality rates among COVID-19 patients with and those without PD. Fever, cough, fatigue, and anorexia existed as the most common manifestations with rates of 72.72%, 66.99%, 61.58%, and 52.55%, respectively. | [68] |
Systematic review aimed to determine the influence of factors connected with COVID-19 in PD patients. | Literature research up to November 2020 (updated until 1 April 2021); finally, six studies (four case–control studies and two cross-sectional studies) in the qualitative and quantitative syntheses. | The following factors were connected with COVID-19 in PD patients: obesity (OR: 1.79) and pulmonary disease (OR: 1.92), COVID-19 contact (OR: 41.77), vitamin D supplementation (OR: 0.50), hospitalization (OR: 11.78), and death (OR: 11.23). The authors did not find any significant correlation between COVID-19 and hypertension, diabetes, cardiopathy, cancer, any cognitive problem, dementia, chronic obstructive pulmonary disease, renal or hepatic disease, smoking, and tremor. | [76] |
Analysis of the relationship between PD and in-hospital outcomes of COVID-19. | A total of 12 studies with 103,874 COVID-19 patients. | PD was connected with poor in-hospital outcomes, OR = 2.64. Subgroup analysis showed that PD was connected with severe COVID-19 OR = 2.61, and mortality from COVID-19 Relative Risk (RR) = 2.63. Meta-regression showed that the association between PD and in-hospital outcomes of COVID-19 was influenced by age, but not by gender, dementia, hypertension, and diabetes. | [77] |
Molecular Target | Example of Drug | Reference |
---|---|---|
Inhibition of NLRP3-dependent programed cell death, called pyroptosis and autophagy regulation, promotion of α-syn clearance, and restoration of proteasome 20 S activity. Reduction in α-syn (Ser129) phosphorylation. | Salidroside | [113,114,115] |
Blocking of the P2X7R/NLRP3 axis triggering a cytokine storm. Reduction in ATP concentration and the activation of IL-1β and IL-6. Prevention of the influx of Ca2+ and the occasion of α-syn mutations. | Lidocaine | [119,150] |
Counteraction glutamine-mediated excitotoxicity by inhibition of calcium influx into the cells by NMDA receptor channel blocking. Inhibition of SARS-CoV-2 viral channel activity, like the Protein E (envelope) cation channel, representing SARS-CoV-2 viroporin involved in its virulence. | Amantadine, Memantine | [131,151] |
Regulation of calcium homeostasis by mGluR5. | Lithium | [138,139,140] |
Switch microglia to anti-inflammatory and neuroprotective M2-phenotype. TLR-4 antagonism, ameliorating cytokine storm. Disruption of SARS-CoV-2 S protein binding to ACE2. Reduction in the phosphorylation/activity of ERK1/2. | Low-Dose Naltrexone | [141,142,143] |
Prevention of the Fenton reaction and the ferroptosis inhibition. | Deferoxamine, Phyto-chelators like Caffeic acid, Curcumin, α-Lipoic acid (ALA), and Phytic acid | [144,146,147,148] |
Scavenging of lipid peroxides and prevention of oxidative damage by lipophilic antioxidants. | Ferrostatin-1, Liproxstatin-1 | [144,149] |
Anti-oxidative effects on the DA neurons in PD by increasing Nrf2 expression, and inhibition of the interaction of ACE2 with the S protein of SARS-CoV-2. | Flavones (Chrysin, Quercetin) | [152,153,154] |
Disease | Case of Patient Description | Ref. |
---|---|---|
DLB | A 68-year-old man after COVID-19 with catatonia symptoms, like sub-stupor, immobility, catalepsy, and rejection. Catatonia appeared for the first time after SARS-CoV-2 infection and did not respond to lorazepam, though the ECT provided relief. Diagnostic imaging, including a DAT scan and 123I-meta-iodobenzylguanidine imaging, showed reduced uptake, leading to the final diagnosis of DLB instead of delirium. | [155] |
MSA | A 65-year-old woman hospitalized for COVID-19 developed ataxia, progressive dizziness, and blurry vision. The evaluation noted rightward nystagmus, resting tremor of the right hand, slowed finger tapping bilaterally, right dysmetria, and a shuffling gait. Lumbar puncture was negative. Brain MRI indicated moderate cerebellar and pontine volume loss with crossed hyperintensity of the pons, known as the “hot cross buns sign”. Videonystagmography proved the cerebellar etiology of her symptoms. MSA with parkinsonian components (MSA-P) was finally diagnosed. The patient reacted positively to therapy with amantadine and carbidopa/levodopa, as well as vestibular rehabilitation and meclizine. Given the close temporal link between SARS-CoV-2 infection and the emergence of MSA features, the authors suggest that this MSA-P case may be related to the COVID-19 infection. | [156] |
RBD | Patients with suspected sleep disorders after acute COVID-19 underwent video-polysomnography (v-PSG). At 60 days post-diagnosis, 4/11 patients (36%) were diagnosed with obstructive sleep apnea (OSA). Also, 4/11 patients showed REM sleep without atonia (RWA), a recognized prodromal stage of RBD, and two additional patients showed an RWA index within the highest range of normality. | [157] |
The results of the case–control studies of 25 patients with previous COVID-19 infection compared with 25 age–sex matched controls who tested negative for COVID-19 before polysomnography. Isolated RWA occurred more frequently in the COVID-19 (9/25 patients, 36%) patients than in the controls (3/25 patients, 12%). | [158] |
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Motyl, J.A.; Gromadzka, G.; Czapski, G.A.; Adamczyk, A. SARS-CoV-2 Infection and Alpha-Synucleinopathies: Potential Links and Underlying Mechanisms. Int. J. Mol. Sci. 2024, 25, 12079. https://doi.org/10.3390/ijms252212079
Motyl JA, Gromadzka G, Czapski GA, Adamczyk A. SARS-CoV-2 Infection and Alpha-Synucleinopathies: Potential Links and Underlying Mechanisms. International Journal of Molecular Sciences. 2024; 25(22):12079. https://doi.org/10.3390/ijms252212079
Chicago/Turabian StyleMotyl, Joanna Agata, Grażyna Gromadzka, Grzegorz Arkadiusz Czapski, and Agata Adamczyk. 2024. "SARS-CoV-2 Infection and Alpha-Synucleinopathies: Potential Links and Underlying Mechanisms" International Journal of Molecular Sciences 25, no. 22: 12079. https://doi.org/10.3390/ijms252212079