A "new" role of amantadines in COVID-19 in patients with Parkinson's disease: results of own comparative study.

Amantadine has begun to be used as a possible alternative in COVID-19 therapy to mitigate its effects. There is anecdotal evidence that patients with Parkinson's disease (PD) treated with amantadine and who test positive for COVID-19 often do not develop clinical manifestations of COVID-19. Objective(s): to compare the clinical course of COVID-19 in patients with PD who took or did not take amantadine sulfate. Patients and methods. A prospective continuous study included 142 patients with PD who were treated in Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy in Kazan from October 2021 to January 2022. Patients filled out a proprietary internally developed questionnaire. Results and discussion. Out of 142 individuals with PD COVID-19 occurred in 77 (54.2%), of which 52.0% had a mild course, 39.0% had a moderate course, 2.6% had a severe course, and in 6.5% the severity of the disease has not been established. Deterioration after COVID-19 infection was noted by 36% of patients: the appearance or increase in motor fluctuations (41%), increased tremor, stiffness or slowness (31%), the appearance of "exhaustion" of the effect of a single dose of levodopa (13%), the appearance or increased dyskinesia (21%), hallucinations (3.5%). Patients taking amantadine sulfate had PD much longer (11.5+/-5.62 years versus 5.12+/-3.24 years) and had a more pronounced (III-IV) stage of the disease. These patients were more likely to experience mild COVID-19 (in 60.87% of cases), in contrast to patients not receiving amantadine sulfate (only in 48.15% of cases). There was no correlation between the severity of COVID-19 and levodopa intake. Conclusion. The results of the study showed that patients with PD taking amantadine sulfate are more likely to have a mild course of COVID-19.Copyright © 2022 Ima-Press Publishing House. All rights reserved.

SARS-CoV-2 Infection Increases the Gene Expression Profile for Alzheimer's Disease Risk

The COVID-19 pandemic is a global outbreak of coronavirus, an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One in five adults who have had COVID-19 in the past was still experiencing any one of the symptoms of long COVID like headache, brain fog, fatigue, and shortness of breath. Up to 30% of individuals with mild to severe infection show diverse neurological symptoms, including dementias. Hence, it is very much important to characterize the neurotropism and neurovirulence of the SARS-CoV-2 virus. This helps us understand the mechanisms involved in initiating inflammation in the brain, further leading to the development of earlyonset Alzheimer's disease and related dementias (ADRDs). In our brain gene expression analysis, we found that severe COVID-19 patients showed increased expression of innate immune response genes and genes that are implicated in AD pathogenesis. To study the infection-induced ADRDs, we used a mouse-adapted strain of the SARS-CoV-2 (MA10) virus to infect mice of different age groups (3, 6, and 20 Months). In this study, we found that aged mice showed evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferoninducible gene Ifi204, and complement genes like C4 and C5AR1. Brain histopathology also showed the AD signature including tau-phosphorylation, tau-oligomerization, and alpha-synuclein expression in aged MA10-infected mice. The results from gene expression profiling of SARS-CoV-2 infected and AD brains and studies with MA10 aged mice show that COVID-19 infection increases the risk of AD in the aged population. Furthermore, this study helps us to understand the crucial molecular markers that are regulated during COVID infection that could act as major players in developing ADRDs. Future studies will be involved in understanding the molecular mechanisms of ADRD in response to COVID infection and developing novel therapies targeting AD.

A "new" role of amantadines in COVID-19 in patients with Parkinson's disease: results of own comparative study

Amantadine has begun to be used as a possible alternative in COVID-19 therapy to mitigate its effects. There is anecdotal evidence that patients with Parkinson's disease (PD) treated with amantadine and who test positive for COVID-19 often do not develop clinical manifestations of COVID-19. Objective(s): to compare the clinical course of COVID-19 in patients with PD who took or did not take amantadine sulfate. Patients and methods. A prospective continuous study included 142 patients with PD who were treated in Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy in Kazan from October 2021 to January 2022. Patients filled out a proprietary internally developed questionnaire. Results and discussion. Out of 142 individuals with PD COVID-19 occurred in 77 (54.2%), of which 52.0% had a mild course, 39.0% had a moderate course, 2.6% had a severe course, and in 6.5% the severity of the disease has not been established. Deterioration after COVID-19 infection was noted by 36% of patients: the appearance or increase in motor fluctuations (41%), increased tremor, stiffness or slowness (31%), the appearance of "exhaustion" of the effect of a single dose of levodopa (13%), the appearance or increased dyskinesia (21%), hallucinations (3.5%). Patients taking amantadine sulfate had PD much longer (11.5+/-5.62 years versus 5.12+/-3.24 years) and had a more pronounced (III-IV) stage of the disease. These patients were more likely to experience mild COVID-19 (in 60.87% of cases), in contrast to patients not receiving amantadine sulfate (only in 48.15% of cases). There was no correlation between the severity of COVID-19 and levodopa intake. Conclusion. The results of the study showed that patients with PD taking amantadine sulfate are more likely to have a mild course of COVID-19.Copyright © 2022 Ima-Press Publishing House. All rights reserved.

A "new" role of amantadines in COVID-19 in patients with Parkinson's disease: results of own comparative study.

Amantadine has begun to be used as a possible alternative in COVID-19 therapy to mitigate its effects. There is anecdotal evidence that patients with Parkinson's disease (PD) treated with amantadine and who test positive for COVID-19 often do not develop clinical manifestations of COVID-19. Objective(s): to compare the clinical course of COVID-19 in patients with PD who took or did not take amantadine sulfate. Patients and methods. A prospective continuous study included 142 patients with PD who were treated in Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy in Kazan from October 2021 to January 2022. Patients filled out a proprietary internally developed questionnaire. Results and discussion. Out of 142 individuals with PD COVID-19 occurred in 77 (54.2%), of which 52.0% had a mild course, 39.0% had a moderate course, 2.6% had a severe course, and in 6.5% the severity of the disease has not been established. Deterioration after COVID-19 infection was noted by 36% of patients: the appearance or increase in motor fluctuations (41%), increased tremor, stiffness or slowness (31%), the appearance of "exhaustion" of the effect of a single dose of levodopa (13%), the appearance or increased dyskinesia (21%), hallucinations (3.5%). Patients taking amantadine sulfate had PD much longer (11.5+/-5.62 years versus 5.12+/-3.24 years) and had a more pronounced (III-IV) stage of the disease. These patients were more likely to experience mild COVID-19 (in 60.87% of cases), in contrast to patients not receiving amantadine sulfate (only in 48.15% of cases). There was no correlation between the severity of COVID-19 and levodopa intake. Conclusion. The results of the study showed that patients with PD taking amantadine sulfate are more likely to have a mild course of COVID-19.Copyright © 2022 Ima-Press Publishing House. All rights reserved.

Nanopore single-molecule analysis of biomarkers: Providing possible clues to disease diagnosis

Biomarker detection has attracted increasing interest in recent years due to the minimally or non-invasive sampling process. Single entity analysis of biomarkers is expected to provide real-time and accurate biological information for early disease diagnosis and prognosis, which is critical to the effective disease treatment and is also important in personalized medicine. As an innovative single entity analysis method, nanopore sensing is a pioneering single-molecule detection technique that is widely used in analytical bioanalytical fields. In this review, we overview the recent progress of nanopore biomarker detection as new approaches to disease diagnosis. In highlighted studies, nanopore was focusing on detecting biomarkers of different categories of communicable and noncommunicable diseases, such as pandemic COVID-19, AIDS, cancers, neurologic diseases, etc. Various sensitive and selective nanopore detecting strategies for different types of biomarkers are summarized. In addition, the challenges, opportunities, and direction for future development of nanopore-based biomarker sensors are also discussed.Copyright © 2023 Elsevier B.V.

Post-COVID anosmia and the expression of pathological proteins in nasal mucosa nerves endings

Introduction: Anosmia and ageusia were observed as frequent neurological complications of SARS-CoV-2 infections. the aim of the study was to elaborate methods for detection of pathological proteins in nerve endings and to evaluate the frequency and intensity of pathological proteins expression in patients with persistent anosmia. Material(s) and Method(s): the study included 249 patients (181 females and 68 males) aged 47 +/-14 years from NeuroCOViD Polyclinic in Poznan observed from April 2021 untill now. the mucosal biopsy was performed using endoscopy from anterior ethmoid cells. the expression of alpha-synuclein was evaluated using immunofuorescence, and amyloid, tau and tDP43 proteins-using immunohistochemistry. Result(s): Anosmia was observed in 42% of patients and cacosmia-in 6%. Ageusia/dysgeusia was observed in 31% cases. in patients with mild clinical course of COViD19-not hospitalized anosmia (45%) and dys-geusia were more frequent (33%), and cacosmia was observed only in this group. in hospitalized patients anosmia was found in 22% of cases, dysgeusia in 13%, and cacosmia was not observed at all. the expression of alpha-synuclein, amyloid, tau and tDP43 proteins was found in nerve bundles, epithelial cells and in surrounding (nerve endings) of gland cells. Conclusion(s): SARS-CoV-2 infection may induce the expression of pathological proteins in olfactory mucosa of post-COViD patients with anosmia.

A functional role for alpha-synuclein in neuroimmune responses.

Alpha-synuclein is a neuronal protein with unclear function but is associated with the pathogenesis of Parkinson's disease and other synucleinopathies. In this review, we discuss the emerging functional role of alpha-synuclein in support of the unique immune responses in the nervous system. Recent data now show that alpha-synuclein functions to support interferon signaling within neurons and is released from neurons to support chemoattraction and activation of local glial cells and infiltrating immune cells. Inflammatory activation and interferon signaling also induce post-translational modifications of alpha-synuclein that are commonly associated with Parkinson's disease pathogenesis. Taken together, emerging data implicate complex interactions between alpha-synuclein and host immune responses that may contribute to the pathogenesis of Parkinson's disease. Additional study of the function of alpha-synuclein in the brain's immune response may provide disease-modifying therapeutic targets for Parkinson's disease in the future.

Dopamine Transmission Imbalance in Neuroinflammation: Perspectives on Long-Term COVID-19.

Dopamine (DA) is a key neurotransmitter in the basal ganglia, implicated in the control of movement and motivation. Alteration of DA levels is central in Parkinson's disease (PD), a common neurodegenerative disorder characterized by motor and non-motor manifestations and deposition of alpha-synuclein (α-syn) aggregates. Previous studies have hypothesized a link between PD and viral infections. Indeed, different cases of parkinsonism have been reported following COVID-19. However, whether SARS-CoV-2 may trigger a neurodegenerative process is still a matter of debate. Interestingly, evidence of brain inflammation has been described in postmortem samples of patients infected by SARS-CoV-2, which suggests immune-mediated mechanisms triggering the neurological sequelae. In this review, we discuss the role of proinflammatory molecules such as cytokines, chemokines, and oxygen reactive species in modulating DA homeostasis. Moreover, we review the existing literature on the possible mechanistic interplay between SARS-CoV-2-mediated neuroinflammation and nigrostriatal DAergic impairment, and the cross-talk with aberrant α-syn metabolism.

Are patients with Parkinson's disease at a lower risk of catching the common cold? Propensity score matching.

INTRODUCTION: Accumulating evidence indicating that inflammatory responses play crucial roles in Parkinson's disease (PD) development provided a hypothesis that physiological alpha-synuclein may contribute to inflammatory responses against infections during non-advanced stages of PD. Thus, we examined the risk of catching a common cold in patients with PD as compared to other common brain diseases. METHODS: We extracted PD (non-advanced; without dementia) and control (AD: Alzheimer's disease, migraine, epilepsy, and ischemic stroke) patient data from insurance claim data available between 2010 and 2021. After confirming the clinical PD diagnosis, we investigated factors associated with cold diagnoses and used propensity score matching to identify differences in the incidence of colds between PD and control patients. RESULTS: Diagnosis of colds in PD patients (n = 726) and controls (AD = 377, migraine = 1019, epilepsy = 3414, ischemic stroke = 6943) was found in 1186 (9.5%) patients, which was independently associated with being female (odds ratio: OR 1.59; 95%CI 1.41-1.79; P < 0.0001), follow-up by neurologists (OR 1.30; 95%CI 1.15-1.48; P < 0.0001), diagnosis of PD (OR 0.30; 95%CI 0.20-0.45; P < 0.0001) and COVID-19 pandemic period (OR 0.58; 95%CI 0.47-0.72; P < 0.0001). After propensity score matching, the incidence of colds was significantly lower in PD (3.4%) versus in controls; AD (9.8%; P < 0.0001), migraine (13.3%; P < 0.0001), epilepsy (11.0%; P < 0.0001), ischemic stroke (8.8%; P < 0.0001). CONCLUSIONS: Patients with PD were less likely to be diagnosed with colds. However, several confounding factors will need to be examined. Moreover, alpha-synuclein may provide protective resistance to viral infections by activating the immune system due to chronic inflammation in non-advanced PD patients.

Does the SARS-CoV-2 Spike Receptor-Binding Domain Hamper the Amyloid Transformation of Alpha-Synuclein after All?

Interactions of key amyloidogenic proteins with SARS-CoV-2 proteins may be one of the causes of expanding and delayed post-COVID-19 neurodegenerative processes. Furthermore, such abnormal effects can be caused by proteins and their fragments circulating in the body during vaccination. The aim of our work was to analyze the effect of the receptor-binding domain of the coronavirus S-protein domain (RBD) on alpha-synuclein amyloid aggregation. Molecular modeling showed that the predicted RBD complex with monomeric alpha-synuclein is stable over 100 ns of molecular dynamics. Analysis of the interactions of RBD with the amyloid form of alpha-synuclein showed that during molecular dynamics for 200 ns the number of contacts is markedly higher than that for the monomeric form. The formation of the RBD complex with the alpha-synuclein monomer was confirmed immunochemically by immobilization of RBD on its specific receptor ACE2. Changes in the spectral characteristics of the intrinsic tryptophans of RBD and hydrophobic dye ANS indicate an interaction between the monomeric proteins, but according to the data of circular dichroism spectra, this interaction does not lead to a change in their secondary structure. Data on the kinetics of amyloid fibril formation using several spectral approaches strongly suggest that RBD prevents the amyloid transformation of alpha-synuclein. Moreover, the fibrils obtained in the presence of RBD showed significantly less cytotoxicity on SH-SY5Y neuroblastoma cells.

On a New Paradigm of the Development of Neurodegenerative Diseases by the Example of Alzheimer's Disease and Parkinson's Disease

The role of neuronal inflammation developing during the formation of amyloid plaques and Lewy bodies is investigated. The influence of various exogenous and endogenous factors on the development of neuroinflammation is established, but the role of various infectious agents in the development of this process is much less studied. Today, the existence of a universal trigger mechanism of the neurodegenerative process is obvious: a specific pathogen of a bacterial or viral nature (including long-term persistent in nervous tissue in a latent state), reactivating, penetrates into certain cerebral structures, where it is influenced by either A beta or resident macrophages of the central nervous system, which, in turn, are activated and induce the release of proinflammatory cytokines, leading to the development of neuronal inflammation, autophagy and neurodegeneration. The reactivation of latent infection, such as herpes, in APOE4 carriers significantly increases the risk of development of Alzheimer's disease. Class-II genes of the HLA locus (HLA II) may be related to the progression of neurodegenerative diseases. An increase in iron levels in the glia is induced by inflammation, which leads to neurodegeneration. Disruption of the homeostasis of redox-active metals, iron and copper, is an integral part of the pathogenesis of Alzheimer's disease and Parkinson's disease. The developing neuroinflammation leads to intensification of the processes of peroxidation, oxidation of metals and the development of ferroptosis.

Post-COVID-19 Parkinsonism and Parkinson's Disease Pathogenesis: The Exosomal Cargo Hypothesis.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.

Norovirus Intestinal Infection and Lewy Body Disease in an Older Patient with Acute Cognitive Impairment.

We present a case report on an older woman with unspecific symptoms and predominant long-term gastrointestinal disturbances, acute overall health deterioration with loss of autonomy for daily activities, and cognitive impairment. Autopsy revealed the presence of alpha-synuclein deposits spread into intestinal mucosa lesions, enteric plexuses, pelvic and retroperitoneal nerves and ganglia, and other organs as well as Lewy pathology in the central nervous system (CNS). Moreover, we isolated norovirus from the patient, indicating active infection in the colon and detected colocalization of norovirus and alpha-synuclein in different regions of the patient's brain. In view of this, we report a concomitant norovirus infection with synthesis of alpha-synuclein in the gastrointestinal mucosa and Lewy pathology in the CNS, which might support Braak's hypothesis about the pathogenic mechanisms underlying synucleinopathies.

Upregulating Human Cathelicidin Antimicrobial Peptide LL-37 Expression May Prevent Severe COVID-19 Inflammatory Responses and Reduce Microthrombosis.

COVID-19 is characterized by hyperactivation by inflammatory cytokines and recruitment of macrophages, neutrophils, and other immune cells, all hallmarks of a strong inflammatory response that can lead to severe complications and multi-organ damage. Mortality in COVID-19 patients is associated with a high prevalence of neutrophil extracellular trap (NET) formation and microthrombosis that are exacerbated by hyperglycemia, diabetes, and old age. SARS-CoV-2 infection in humans and non-human primates have revealed long-term neurological consequences of COVID-19, possibly concomitant with the formation of Lewy bodies in the brain and invasion of the nervous system via the olfactory bulb. In this paper, we review the relevance of the human cathelicidin LL-37 in SARS-CoV-2 infections. LL-37 is an immunomodulatory, host defense peptide with direct anti-SARS-CoV-2 activity, and pleiotropic effects on the inflammatory response, neovascularization, Lewy body formation, and pancreatic islet cell function. The bioactive form of vitamin D and a number of other compounds induce LL-37 expression and one might predict its upregulation, could reduce the prevalence of severe COVID-19. We hypothesize upregulation of LL-37 will act therapeutically, facilitating efficient NET clearance by macrophages, speeding endothelial repair after inflammatory tissue damage, preventing α-synuclein aggregation, and supporting blood-glucose level stabilization by facilitating insulin release and islet ß-cell neogenesis. In addition, it has been postulated that LL-37 can directly bind the S1 domain of SARS-CoV-2, mask angiotensin converting enzyme 2 (ACE2) receptors, and limit SARS-CoV-2 infection. Purposeful upregulation of LL-37 could also serve as a preventative and therapeutic strategy for SARS-CoV-2 infections.

Role of SARS-CoV-2 in Modifying Neurodegenerative Processes in Parkinson's Disease: A Narrative Review.

The COVID-19 pandemic, caused by SARS-CoV-2, continues to impact global health regarding both morbidity and mortality. Although SARS-CoV-2 primarily causes acute respiratory distress syndrome (ARDS), the virus interacts with and influences other organs and tissues, including blood vessel endothelium, heart, gastrointestinal tract, and brain. We are learning much about the pathophysiology of SARS-CoV-2 infection; however, we are just beginning to study and understand the long-term and chronic health consequences. Since the pandemic's beginning in late 2019, older adults, those with pre-existing illnesses, or both, have an increased risk of contracting COVID-19 and developing severe COVID-19. Furthermore, older adults are also more likely to develop the neurodegenerative disorder Parkinson's disease (PD), with advanced age as the most significant risk factor. Thus, does SARS-CoV-2 potentially influence, promote, or accelerate the development of PD in older adults? Our initial focus was aimed at understanding SARS-CoV-2 pathophysiology and the connection to neurodegenerative disorders. We then completed a literature review to assess the relationship between PD and COVID-19. We described potential molecular and cellular pathways that indicate dopaminergic neurons are susceptible, both directly and indirectly, to SARS-CoV-2 infection. We concluded that under certain pathological circumstances, in vulnerable persons-with-Parkinson's disease (PwP), SARS-CoV-2 acts as a neurodegenerative enhancer to potentially support the development or progression of PD and its related motor and non-motor symptoms.

Microgliosis and neuronal proteinopathy in brain persist beyond viral clearance in SARS-CoV-2 hamster model.

BACKGROUND: Neurological symptoms such as cognitive decline and depression contribute substantially to post-COVID-19 syndrome, defined as lasting symptoms several weeks after initial SARS-CoV-2 infection. The pathogenesis is still elusive, which hampers appropriate treatment. Neuroinflammatory responses and neurodegenerative processes may occur in absence of overt neuroinvasion. METHODS: Here we determined whether intranasal SARS-CoV-2 infection in male and female syrian golden hamsters results in persistent brain pathology. Brains 3 (symptomatic) or 14 days (viral clearance) post infection versus mock (n = 10 each) were immunohistochemically analyzed for viral protein, neuroinflammatory response and accumulation of tau, hyperphosphorylated tau and alpha-synuclein protein. FINDINGS: Viral protein in the nasal cavity led to pronounced microglia activation in the olfactory bulb beyond viral clearance. Cortical but not hippocampal neurons accumulated hyperphosphorylated tau and alpha-synuclein, in the absence of overt inflammation and neurodegeneration. Importantly, not all brain regions were affected, which is in line with selective vulnerability. INTERPRETATION: Thus, despite the absence of virus in brain, neurons develop signatures of proteinopathies that may contribute to progressive neuronal dysfunction. Further in depth analysis of this important mechanism is required. FUNDING: Federal Ministry of Health (BMG; ZMV I 1-2520COR501), Federal Ministry of Education and Research (BMBF 01KI1723G), Ministry of Science and Culture of Lower Saxony in Germany (14 - 76103-184 CORONA-15/20), German Research Foundation (DFG; 398066876/GRK 2485/1), Luxemburgish National Research Fund (FNR, Project Reference: 15686728, EU SC1-PHE-CORONAVIRUS-2020 MANCO, no > 101003651).

SARS-CoV-2 Proteins Interact with Alpha Synuclein and Induce Lewy Body-like Pathology In Vitro.

Growing cases of patients reported have shown a potential relationship between (severe acute respiratory syndrome coronavirus 2) SARS-CoV-2 infection and Parkinson's disease (PD). However, it is unclear whether there is a molecular link between these two diseases. Alpha-synuclein (α-Syn), an aggregation-prone protein, is considered a crucial factor in PD pathology. In this study, bioinformatics analysis confirmed favorable binding affinity between α-Syn and SARS-CoV-2 spike (S) protein and nucleocapsid (N) protein, and direct interactions were further verified in HEK293 cells. The expression of α-Syn was upregulated and its aggregation was accelerated by S protein and N protein. It was noticed that SARS-CoV-2 proteins caused Lewy-like pathology in the presence of α-Syn overexpression. By confirming that SARS-CoV-2 proteins directly interact with α-Syn, our study offered new insights into the mechanism underlying the development of PD on the background of COVID-19.

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.

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease, afflicting ~10 million people worldwide. Although several genes linked to PD are currently identified, PD remains primarily an idiopathic disorder. Neuronal protein α-synuclein is a major player in disease progression of both genetic and idiopathic forms of PD. However, it cannot alone explain underlying pathological processes. Recent studies demonstrate that many other risk factors can accelerate or further worsen brain dysfunction in PD patients. Several PD models, including non-mammalian eukaryotic organisms, have been developed to identify and characterize these factors. This review discusses recent findings in three PD model organisms, i.e., yeast, Drosophila, and Caenorhabditis elegans, that opened new mechanisms and identified novel contributors to this disorder. These non-mammalian models share many conserved molecular pathways and cellular processes with humans. New players affecting PD pathogenesis include previously unknown genes/proteins, novel signaling pathways, and low molecular weight substances. These findings might respond to the urgent need to discover novel drug targets for PD treatment and new biomarkers for early diagnostics of this disease. Since the study of neurodegeneration using simple eukaryotic organisms brought a huge amount of information, we include only the most recent or the most important relevant data.