Exploration of the Shared Molecular Mechanisms between COVID-19 and Neurodegenerative Diseases through Bioinformatic Analysis.

The COVID-19 pandemic has caused millions of deaths and remains a major public health burden worldwide. Previous studies found that a large number of COVID-19 patients and survivors developed neurological symptoms and might be at high risk of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). We aimed to explore the shared pathways between COVID-19, AD, and PD by using bioinformatic analysis to reveal potential mechanisms, which may explain the neurological symptoms and degeneration of brain that occur in COVID-19 patients, and to provide early intervention. In this study, gene expression datasets of the frontal cortex were employed to detect common differentially expressed genes (DEGs) of COVID-19, AD, and PD. A total of 52 common DEGs were then examined using functional annotation, protein-protein interaction (PPI) construction, candidate drug identification, and regulatory network analysis. We found that the involvement of the synaptic vesicle cycle and down-regulation of synapses were shared by these three diseases, suggesting that synaptic dysfunction might contribute to the onset and progress of neurodegenerative diseases caused by COVID-19. Five hub genes and one key module were obtained from the PPI network. Moreover, 5 drugs and 42 transcription factors (TFs) were also identified on the datasets. In conclusion, the results of our study provide new insights and directions for follow-up studies of the relationship between COVID-19 and neurodegenerative diseases. The hub genes and potential drugs we identified may provide promising treatment strategies to prevent COVID-19 patients from developing these disorders.

Acute Worsening of Atypical Parkinson's Syndrome After Receiving Second Dose of Moderna COVID-19 Vaccine.

INTRODUCTION: Atypical Parkinson's syndromes are a rare set of neurodegenerative conditions in which a patient experiences the typical symptoms of Parkinson's disease, in addition to various other unrelated issues. CASE PRESENTATION: We present the case of a 71-year-old White man with a 1-year history of weakness and upper extremity tremors that, per patient report, rapidly worsened after receiving the second dose of the Moderna COVID-19 vaccine. His symptoms were consistent with an asymmetric atypical Parkinson's disease, with electromyogram results indicating chronic motor neuron involvement. DISCUSSION: There have been multiple reports of deterioration in patients with Parkinson's disease and atypical Parkinson's syndromes in response to contracting COVID-19. However, there are few, if any, case reports that describe an acute change in Parkinson-related symptoms in association with the COVID-19 vaccines. CONCLUSIONS: As the pandemic continues, we must continue to remain vigilant as we learn more about the long-lasting effects of the virus and vaccines.

Molecular mechanisms highlighting the potential role of COVID-19 in the development of neurodegenerative diseases.

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the pulmonary manifestations, COVID-19 patients may present a wide range of neurological disorders as extrapulmonary presentations. In this view, several studies have recently documented the worsening of neurological symptoms within COVID-19 morbidity in patients previously diagnosed with neurodegenerative diseases (NDs). Moreover, several cases have also been reported in which the patients presented parkinsonian features after initial COVID-19 symptoms. These data raise a major concern about the possibility of communication between SARS-CoV-2 infection and the initiation and/or worsening of NDs. In this review, we have collected compelling evidence suggesting SARS-CoV-2, as an environmental factor, may be capable of developing NDs. In this respect, the possible links between SARS-CoV-2 infection and molecular pathways related to most NDs and the pathophysiological mechanisms of the NDs such as Alzheimer's disease, vascular dementia, frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis will be explained.

COVID-19: The cynosure of rise of Parkinson's disease.

Parkinson's disease (PD) is one of the most common age-related disorders globally. The pathophysiological mechanisms and precipitating factors underlying PD manifestations, including genetic and environmental parameters, inflammation/stress and ageing, remain elusive. Speculations about whether the Coronavirus Disease 2019 (Covid-19) pandemic could be a pivotal factor in affecting the prevalence and severity of PD or triggering a wave of new-onset parkinsonism in both the near and distant future have recently become very popular, with researchers wondering if there is a changing trend in current parkinsonism cases. Could the current understanding of the Covid-19 pathophysiology provide clues for an impending rise of parkinsonism cases in the future? Are there any lessons to learn from previous pandemics? Our aim was to look into these questions and available current literature in order to investigate if Covid-19 could constitute a cardinal event affecting the parkinsonism landscape.

Microbes and Parkinson's disease: from associations to mechanisms.

Parkinson's disease (PD) is a neurodegenerative disorder influenced by both genetic and environmental factors. The mechanisms leading to neurodegeneration in PD are still under investigation, with several mechanistic models currently proposed. A number of microorganisms have been associated with increased risk of PD in humans, and recent research using newly developed models has begun to elucidate how these microbes may factor into disease development. Newly identified roles for PD-associated genes in host-microbe interactions and response to infections have also recently been uncovered, providing further evidence for microbial contributions to PD. Here we summarize these recent advances in the field and discuss them in the context of both historical and emerging hypotheses for PD development, with a particular focus on the application of rodent models as systems allowing for mechanistic hypothesis testing.

The Nigral Coup in Parkinson's Disease by α-Synuclein and Its Associated Rebels.

The risk of Parkinson's disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson's disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.

Human coronaviruses in idiopathic Parkinson's disease: Implications of SARS-CoV-2's modulation of the host's transcriptome.

OBJECTIVE: A recent study on the effects of SARS-CoV-2 infection on the host's transcriptome indicated the perturbation of several pathways associated with neurodegeneration, including but not limited to Parkinson's and Huntington's diseases. The purpose of this study was to determine overlapping pathways between iPD vs. Controls and those associated with SARS-CoV-2 infection. METHODS: Gene set enrichment analyses (GSEA) were performed on gene expression data from tissues donated by idiopathic Parkinson's disease patients (iPD). These included dorsal motor nucleus of the vagus (DMNV), substantia nigra (SN), whole blood (WB) and peripheral blood mononuclear cell samples (PBMC). Enriched pathways detected by GSEA results were subsequently compared to (a) those retrieved by two independently constructed SARS-CoV-2 - host interactomes, as well as (b) previously published pathway data. For all analyses, a false discovery rate (FDR) <0.05 was considered statistically significant. RESULTS: Analysis of iPD data revealed multiple immune response and viral parasitism -related pathways (FDR < 0.05). Head-to-head comparisons as well as confirmatory analyses revealed several pathways and gene ontology (GO) terms overlapping between iPD tissues and SARS-CoV-2 induced transcriptomic changes: "Parkinson's Disease" and "Huntington's Disease" (overlapping in DMNV, ION, SN, and WB; FDR < 0.05), "NAFLD" (overlapping in DMNV, SN, PBMC and WB; FDR < 0.05), mRNA surveillance and proteostasis pathways (All datasets; FDR < 0.5), among others. CONCLUSION: The overlap noted in this comparative transcriptomic study outlines the potential contribution of human coronaviruses in the pathogenesis of iPD. Furthermore, given SARS-CoV-2's neuroinvasive potential, closer scrutiny is warranted towards its contribution in the long-term development of neurodegenerative disease.

Genetic Exchange of Lung-Derived Exosome to Brain Causing Neuronal Changes on COVID-19 Infection.

The pandemic of novel coronavirus 2 (SARS-CoV-2) has made global chaos for normal human living. Despite common COVID-19 symptoms, variability in clinical phenotypes was reported worldwide. Reports on SARS-CoV-2 suggest causing neurological manifestation. In addition, the susceptibility of SARS-CoV-2 in patients with neurodegenerative diseases and its complexity are largely unclear. Here, we aimed to demonstrate the possible transport of exosome from SARS-CoV-2-infected lungs to the brain regions associated with neurodegenerative diseases using multiple transcriptome datasets of SARS-CoV-2-infected lungs, RNA profiles from lung exosome, and gene expression profiles of the human brain. Upon transport, the transcription factors localized in the exosome regulate genes at lateral substantia nigra, medial substantia nigra, and superior frontal gyrus regions of Parkinson's disease (PD) and frontal cortex, hippocampus, and temporal cortex of Alzheimer's disease (AD). On SARS-CoV-2 infection, BCL3, JUND, MXD1, IRF2, IRF9, and STAT1 transcription factors in the exosomes influence the neuronal gene regulatory network and accelerate neurodegeneration. STAT1 transcription factor regulates 64 PD genes at lateral substantia nigra, 65 at superior frontal gyrus, and 19 at medial substantia nigra. Similarly, in AD, STAT1 regulates 74 AD genes at the temporal cortex, 40 genes at the hippocampus, and 16 genes at the frontal cortex. We further demonstrate that dysregulated neuronal genes showed involvement in immune response, signal transduction, apoptosis, and stress response process. In conclusion, SARS-CoV-2 may dysregulate neuronal gene regulatory network through exosomes that attenuate disease severity of neurodegeneration.

Possible Link between SARS-CoV-2 Infection and Parkinson's Disease: The Role of Toll-Like Receptor 4.

Parkinson's disease (PD) is the most common neurodegenerative motor disorder characterized by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain, depletion of dopamine (DA), and impaired nigrostriatal pathway. The pathological hallmark of PD includes the aggregation and accumulation α-synuclein (α-SYN). Although the precise mechanisms underlying the pathogenesis of PD are still unknown, the activation of toll-like receptors (TLRs), mainly TLR4 and subsequent neuroinflammatory immune response, seem to play a significant role. Mounting evidence suggests that viral infection can concur with the precipitation of PD or parkinsonism. The recently identified coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of ongoing pandemic coronavirus disease 2019 (COVID-19), responsible for 160 million cases that led to the death of more than three million individuals worldwide. Studies have reported that many patients with COVID-19 display several neurological manifestations, including acute cerebrovascular diseases, conscious disturbance, and typical motor and non-motor symptoms accompanying PD. In this review, the neurotropic potential of SARS-CoV-2 and its possible involvement in the pathogenesis of PD are discussed. Specifically, the involvement of the TLR4 signaling pathway in mediating the virus entry, as well as the massive immune and inflammatory response in COVID-19 patients is explored. The binding of SARS-CoV-2 spike (S) protein to TLR4 and the possible interaction between SARS-CoV-2 and α-SYN as contributing factors to neuronal death are also considered.

Mitochondrial nanomedicine: Subcellular organelle-specific delivery of molecular medicines.

As mitochondria network together to act as the master sensors and effectors of apoptosis, ATP production, reactive oxygen species management, mitophagy/autophagy, and homeostasis; this organelle is an ideal target for pharmaceutical manipulation. Mitochondrial dysfunction contributes to many diseases, for example, ß-amyloid has been shown to interfere with mitochondrial protein import and induce apoptosis in Alzheimer's Disease while some forms of Parkinson's Disease are associated with dysfunctional mitochondrial PINK1 and Parkin proteins. Mitochondrial medicine has applications in the treatment of an array of pathologies from cancer to cardiovascular disease. A challenge of mitochondrial medicine is directing therapies to a subcellular target. Nanotechnology based approaches combined with mitochondrial targeting strategies can greatly improve the clinical translation and effectiveness of mitochondrial medicine. This review discusses mitochondrial drug delivery approaches and applications of mitochondrial nanomedicines. Nanomedicine approaches have the potential to drive the success of mitochondrial therapies into the clinic.

Parkinson's Disease Causative Mutation in Vps35 Disturbs Tetherin Trafficking to Cell Surfaces and Facilitates Virus Spread.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra, intraneuronal deposition of misfolded proteins known as Lewy bodies, and chronic neuroinflammation. PD can arise from monogenic mutations, but in most cases, the etiology is unclear. Viral infection is gaining increasing attentions as a trigger of PD. In this study, we investigated whether the PD-causative 620 aspartate (D) to asparagine (N) mutation in the vacuolar protein sorting 35 ortholog (Vps35) precipitated herpes simplex virus (HSV) infection. We observed that ectopic expression of Vps35 significantly reduced the proliferation and release of HSV-1 virions; the D620N mutation rendered Vps35 a partial loss of such inhibitory effects. Tetherin is a host cell protein capable of restricting the spread of encapsulated viruses including HSV-1 and SARS-Cov-2, both of which are implicated in the development of parkinsonism. Compared with cells overexpressing wildtype Vps35, cells expressing mutant Vps35 with D620N had less Tetherin on cell surfaces. Real-time and static cell imaging revealed that Tetherin recycled through Vps35-positive endosomes. Expression of Vps35 with D620N reduced endosomal dynamics and frequency of motile Tetherin-containing vesicles, a sign of defective production of recycling carriers. Our study suggests that the D620N mutation in Vps35 hinders Tetherin trafficking to cell surfaces and facilitates virus spread.

Do Males Affect Twinning Events? A Review of Current Findings/Twin Research Reviews: Monozygotic Twins Discordant for Parkinson's Disease; Fetal Loss in Twin Pregnancies Following Prenatal Diagnosis; Uterine Rupture and Repair in an Early Twin Pregnancy; Twin Study of Affectionate Communication/Human Interest: Conjoined Twins in a Triplet Set; Identical Twin Nurses Deliver Identical Twins; Identical Twins Discordant for COVID-19 Recovery Course; Identical Twins Pass Away from COVID-19; Archeological Finds of Oldest Identical Twins.

Research into the origins of twinning has focused mostly on contributions from the female side of the family. A review of current findings suggests that possible male contributions to twinning events have been overlooked. This section is followed by brief reviews of twin research concerning monozygotic twins discordant for Parkinson's disease, fetal loss in twin pregnancies following prenatal diagnosis, uterine rupture and repair in an early twin pregnancy and a twin study of affectionate communication. The concluding portion of this article presents human interest stories involving twins that are both informative and poignant, namely conjoined twins in a triplet set, identical twin nurses who delivered identical twins, identical twins discordant for COVID-19 recovery course, identical twins who passed away from COVID-19 and archeological finds of the oldest identical twins.