Pathogenesis Of Parkinson's Disease Research Articles

Regulatory Non-coding RNAs Involved in Oxidative Stress and Neuroinflammation: An Intriguing Crosstalk in Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the accumulation of α-synuclein and the degeneration of dopaminergic neurons in the substantia nigra. Although the molecular bases for PD development are not fully recognized, extensive evidence has suggested that the development of PD is strongly associated with neuroinflammation. It is noteworthy that while neuroinflammation might not be a primary factor in all patients with PD, it seems to be a driving force for disease progression, and therefore, exploring the role of pathways involved in neuroinflammation is of great importance. Besides, the importance of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and competing endogenous RNAs (ceRNAs), has been widely studied with a focus on the pathogenesis of PD. However, there is no comprehensive review regarding the role of neuroinflammation-related ncRNAs as prospective biomarkers and therapeutic targets involved in the pathogenesis of PD, even though the number of studies connecting ncRNAs to neuroinflammatory pathways and oxidative stress has markedly increased in the last few years. Hence, the present narrative review intended to describe the crosstalk between regulatory ncRNAs and neuroinflammatory targets with respect to PD to find and propose novel combining biomarkers or therapeutic targets in clinical settings.

LRRK2; Communicative Role in the Treatment of Parkinson's Disease and Ulcerative Colitis Overlapping.

Involvement of gastrointestinal inflammation in Parkinson's disease (PD) pathogenesis and movement have progressively emerged. Inflammation is involved in the etiology of both PD and inflammatory bowel disease (IBD). Transformations in leucine-rich recurrent kinase 2 (LRRK2) are among the best hereditary supporters of IBD and PD. Elevated levels of LRRK2 have been reported in stimulated colonic tissue from IBD patients and peripheral invulnerable cells from irregular PD patients; thus, it is thought that LRRK2 directs inflammatory cycles. Since its revelation, LRRK2 has been seriously linked in neurons, albeit various lines of proof affirmed that LRRK2 is profoundly communicated in invulnerable cells. Subsequently, LRRK2 might sit at a junction by which stomach inflammation and higher LRRK2 levels in IBD might be a biomarker of expanded risk for inconsistent PD or potentially may address a manageable helpful objective in incendiary sicknesses that increment the risk of PD. Here, we discuss how PD and IBD share covering aggregates, especially regarding LRRK2 and present inhibitors, which could be a helpful objective in ongoing treatments. English data were obtained from Google Scholar, PubMed, Scopus, and Cochrane library studies published between 1990-December 2022. Inhibitors of the LRRK2 pathway can be considered as the novel treatment approaches for IBD and PD treatment. Common mediators and pathways are involved in the pathophysiology of IBD and PD, which are majorly correlated with inflammatory situations. Such diseases could be used for further clinical investigations.

Role of Glutathione in Parkinson's Disease Pathophysiology and Therapeutic Potential of Polyphenols.

Oxidative stress is recognized to have a central role in the initiation and progression of Parkinson's disease (PD). Within the brain, neurons are particularly sensitive to oxidation due in part to their weak intrinsic antioxidant defense. Theoretically, neurons mostly depend on neighboring astrocytes to provide antioxidant protection by supplying cysteine-containing products for glutathione (GSH) synthesis. Astrocytes and neurons possess several amino acid transport systems for GSH and its precursors. Indeed, GSH is the most abundant intrinsic antioxidant in the central nervous system. The GSH depletion and/or alterations in its metabolism in the brain contribute to the pathogenesis of PD. Noteworthy, polyphenols possess potent antioxidant activity and can augment the GSH redox system. Numerous in vitro and in vivo studies have indicated that polyphenols exhibit potent neuroprotective effects in PD. Epidemiological studies have found an association between the consumption of dietary polyphenols and a lower PD risk. In this review, we summarize current knowledge on the biosynthesis and metabolism of GSH in the brain, with an emphasis on their contribution and therapeutic potential in PD. In particular, we focus on polyphenols that can increase brain GSH levels against PD. Furthermore, some current challenges and future perspectives for polyphenol-based therapies are also discussed.

Olfactory deficit and gastrointestinal dysfunction precede motor abnormalities in alpha-Synuclein G51D knock-in mice

Parkinson's disease (PD) is typically a sporadic late-onset disorder, which has made it difficult to model in mice. Several transgenic mouse models bearing mutations in SNCA, which encodes alpha-Synuclein (α-Syn), have been made, but these lines do not express SNCA in a physiologically accurate spatiotemporal pattern, which limits the ability of the mice to recapitulate the features of human PD. Here, we generated knock-in mice bearing the G51D SNCA mutation. After establishing that their motor symptoms begin at 9 mo of age, we then sought earlier pathologies. We assessed the phosphorylation at Serine 129 of α-Syn in different tissues and detected phospho-α-Syn in the olfactory bulb and enteric nervous system at 3 mo of age. Olfactory deficit and impaired gut transit followed at 6 mo, preceding motor symptoms. The SncaG51D mice thus parallel the progression of human PD and will enable us to study PD pathogenesis and test future therapies.

Bifunctional Inhibitor Lentinan Inhibits Fibrillogenesis of Amyloid-β Protein and α-Synuclein and Alleviates Their Cytotoxicity: In Vitro and In Vivo Studies.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases in the world. Misfolding of β-amyloid (Aβ) and α-synuclein (α-syn) and subsequent fibril formation are closely associated with the pathogenesis of AD and PD, respectively. Lentinan is a natural product commonly used in medicine and dietary supplements. It has potential antitumor, anti-inflammatory, and antiviral effects, but the underlying mechanism of its action on AD and PD remains unclear. In this study, lentinan inhibited the formation of Aβ and α-syn fibers in a dose-dependent manner and disrupted their mature fibers. Lentinan inhibited the conversion of Aβ and α-syn conformations to β-sheet-rich conformations. Additionally, lentinan protected Caenorhabditis elegans against damage caused by the accumulation of Aβ and α-syn aggregation and prolonged their lifespan. Notably, the beneficial effects of lentinan in AD and PD mice were also demonstrated, including ameliorating the cognitive and memory impairments in AD mice and behavioral deficits in PD mice. Finally, molecular interactions between lentinan and Aβ/α-syn pentamers were also explored using molecular docking.

REV-ERBα Mitigates Astrocyte Activation and Protects Dopaminergic Neurons from Damage.

Parkinson's disease (PD) is characterized by astrocyte activation and disruptions in circadian rhythm. Within the astrocyte population, two distinct reactive states exist: A1 and A2. A1 astrocytes are associated with neurotoxicity and inflammation, while A2 astrocytes exhibit neuroprotective functions. Our investigation focused on the role of REV-ERBα, a member of the nuclear receptor superfamily and a key regulator of the circadian clock, in astrocyte activation. We observed that REV-ERBα expression in A1 astrocytes was reduced to one-third of its normal level. Notably, activation of REV-ERBα prompted a transformation of astrocytes from A1 to A2. Mechanistically, REV-ERBα inhibition was linked to the classical NF-κB pathway, while it concurrently suppressed the STAT3 pathway. Furthermore, astrocytes with low REV-ERBα expression were associated with dopaminergic neurons apoptosis. Intriguingly, the opposite effect was observed when using a REV-ERBα agonist, which mitigated astrocyte activation and reduced dopaminergic neuron damage by 50%. In summary, our study elucidates the pivotal role of REV-ERBα in modulating astrocyte function and its potential implications in PD pathogenesis.

The Neuroprotective Effects of Agmatine on Parkinson's Disease: Focus on Oxidative Stress, Inflammation and Molecular Mechanisms.

Agmatine (AGM), a naturally occurring polyamine derived from L-arginine, has shown significant potential for neuroprotection in Parkinson's Disease (PD) due to its multifaceted biological activities, including antioxidant, anti-inflammatory, and anti-apoptotic effects. This review explores the therapeutic potential of AGM in treating PD, focusing on its neuroprotective mechanisms and evidence from preclinical studies. AGM has been demonstrated to mitigate the neurotoxic effects of rotenone (ROT) by improving motor function, reducing oxidative stress markers, and decreasing levels of pro-inflammatory cytokines in animal models. Additionally, AGM protects against the loss of TH + neurons, crucial for dopamine synthesis. The neuroprotective properties of AGM are attributed to its ability to modulate several key pathways implicated in PD pathogenesis, such as inhibition of NMDA receptors, activation of Nrf2, and suppression of the HMGB1/ RAGE/ TLR4/ MyD88/ NF-κB signaling cascade. Furthermore, the potential of agmatine to promote neurorestoration is highlighted by its role in enhancing neuroplasticity elements such as CREB, BDNF, and ERK1/2. This review highlights agmatine's promising therapeutic potential in PD management, suggesting that it could offer both symptomatic relief and neuroprotective benefits, thereby modifying the disease course and improving the quality of life for patients. Further research is warranted to translate these preclinical findings into clinical applications.

Insight into brain metallothioneins from bidirectional Zn2+ signaling in synaptic dynamics.

The basal levels as the labile Zn2+ pools in the extracellular and intracellular compartments are in the range of ∼10nM and ∼100 pM, respectively. The influx of extracellular Zn2+ is used for memory via cognitive activity and is regulated for synaptic plasticity, a cellular mechanism of memory. When Zn2+ influx into neurons excessively occurs, however, it becomes a critical trigger for cognitive decline and neurodegeneration, resulting in acute and chronic pathogenesis. Aging, a biological process, generally accelerates vulnerability to neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). The basal level of extracellular Zn2+ is age relatedly increased in the rat hippocampus, and the influx of extracellular Zn2+ contributes to accelerating vulnerability to the AD and PD pathogenesis in experimental animals with aging. Metallothioneins (MTs) are Zn2+-binding proteins for cellular Zn2+ homeostasis and involved in not only supplying functional Zn2+ required for cognitive activity, but also capturing excess (toxic) Zn2+ involved in cognitive decline and neurodegeneration. Therefore, it is estimated that regulation of MT synthesis is involved in both neuronal activity and neuroprotection. The present report provides recent knowledge regarding the protective/preventive potential of MT synthesis against not only normal aging but also the AD and PD pathogenesis in experimental animals, focused on MT function in bidirectional Zn2+ signaling in synaptic dynamics.

The diagnostic value of neutrophil to lymphocyte ratio, albumin to fibrinogen ratio, and lymphocyte to monocyte ratio in Parkinson's disease: a retrospective study.

Parkinson's disease (PD) is a prevalent disorder of the central nervous system, marked by the degeneration of dopamine (DA) neurons in the ventral midbrain. In the pathogenesis of PD, inflammation hypothesis has been concerned. This study aims to investigate clinical indicators of peripheral inflammation in PD patients and to explore the diagnostic value of neutrophil-to-lymphocyte ratio (NLR), albumin-to-fibrinogen ratio (AFR), and lymphocyte-to-monocyte ratio (LMR) in assessing PD risk. This study included 186 patients with PD and 201 matched healthy controls (HC) with baseline data. Firstly, the differences of hematological indicators between PD group and healthy participants were compared and analyzed. Univariate and multivariate regression analyses were then conducted. Smooth curve fitting was applied to further validate the relationships between NLR, LMR, AFR, and PD. Subsequently, subgroup analysis was conducted in PD group according to different duration of disease and Hoehn and Yahr (H&Y) stage, comparing differences in clinical indicators. Finally, the receiver operating characteristic (ROC) curve was employed to assess the diagnostic value of NLR, LMR, and AFR in PD. Compared to the HC group, the PD group showed significantly higher levels of hypertension, diabetes, neutrophil count, monocyte count, CRP, homocysteine, fibrinogen, and NLR. Conversely, levels of LMR, AFR, lymphocyte count, HDL, LDL, TG, TC, uric acid, and albumin were significantly lower. The multivariate regression model indicated that NLR (OR = 1.79, 95% CI: 1.39-2.31, p < 0.001), LMR (OR = 0.75, 95% CI: 0.66-0.85, p < 0.001), and AFR (OR = 0.79, 95% CI: 0.73-0.85, p < 0.001) were significant factors associated with PD. Smooth curve fitting revealed that NLR was positively linked to PD risk, whereas AFR and LMR were inversely associated with it. In ROC curve analysis, the AUC of AFR was 0.7290, the sensitivity was 63.98%, and the specificity was 76.00%. The AUC of NLR was 0.6200, the sensitivity was 50.54%, and the specificity was 71.50%. The AUC of LMR was 0.6253, the sensitivity was 48.39%, and the specificity was 73.00%. The AUC of the combination was 0.7498, the sensitivity was 74.19%, and the specificity was 64.00%. Our findings indicate that NLR, LMR, and AFR are significantly associated with Parkinson's disease and may serve as diagnostic markers.

Potent Small Molecules Inhibitors Discovery through Ligand-based Modelling for Effective Treatment of Parkinson’s Disease

Background: Parkinson’s disease (PD) is a chronic neurodegenerative disease affecting mostly aged people. The disease's symptoms develop gradually over time and include tremors, bradykinesia, rigidity, and postural instability. Current treatment options for PD are only symptom-targeted. Prolyl oligopeptidase (POP) is a serine protease enzymes implicated in PD pathogenesis via an increase in the aggregation of α-synuclein protein in the brain. Aim: This study aims to identify potent anti-PD ligands with inhibitory potential against POP Methods: Ligand-based pharmacophore modeling, Glide extra precision (XP) docking, and post-simulation analysis methods were used. Results: The adopted ligand-based (LB) modeling generated pharmacophoric features, including 1 hydrophobic group, 1 positive ionizable group, 2 aromatic rings, and 2 hydrogen bond acceptors. A total of 23 hits with a Gunner-Henry score of 0.7 and an enrichment factor of 30.24 were obtained as validation protocols, making it an ideal model. The LB model retrieved 177 hit compounds from the 69,543 natural screening ligands available in the Interbioscreen database. Interestingly, ligands 1, 2, 3, 4, and 5 orderly demonstrated higher binding affinities with Glide XP docking of -9.0, -8.8, -8.7, -8.7, -8.7 kcal/mol compared to reference drugs, GSK552 and ZPP with -8.2, and -6.8 kcal/mol respectively. Similarly, their MM/GBSA values were recorded as -54.4, -51.3, -58.4, -49.3, - 33.5, &amp; -32.5 kJ/mol respectively. Further, MD analysis indicated that ligands had higher favorable binding and stability to the receptor. Conclusion: Overall, the study paves the way for developing potential anti-PD therapeutics. The ligands are recommended as adjuvant/single candidate as anti-PD candidates upon further experiment.

Cdc25A phosphatase is activated and mediates neuronal cell death by PUMA via pRb/E2F1 pathway in a model of Parkinson's disease

Parkinson's disease (PD) is a predominant movement disorder caused mainly due to selective loss of the dopaminergic neurons in the substantia nigra pars compacta of the mid brain. There is currently no cure for PD barring treatments to manage symptoms. The reasons might be due to lack of precise understanding of molecular mechanisms leading to neurodegeneration. Aberrant cell cycle activation has been implicated in neuronal death pathways of various neurodegenerative diseases including PD. This study investigates the role of cell cycle regulator Cell division cycle 25A (Cdc25A) in a PD-relevant neuron death model induced by 6-OHDA treatment. We find Cdc25A is rapidly elevated, activated and is playing a key role in neuron death by regulating Rb phosphorylation and E2F1 activity. Knockdown of Cdc25A via shRNA downregulates the levels of pro-apoptotic PUMA, an E2F1 target and cleaved Caspase-3 levels, suggesting Cdc25A may regulate neuronal apoptosis through these effectors. Our work sheds light on the intricate signaling networks involved in neurodegeneration and highlights Cdc25A as a potential therapeutic target for mitigating aberrant cell cycle re-entry underlying PD pathogenesis. These novel insights into molecular mechanisms provide a foundation for future development of neuroprotective strategies to slow or prevent progression of this debilitating disease.

Association of synuclein alpha (SNCA) gene polymorphisms with spontaneous brain activity in patients with Parkinson's disease.

The synuclein alpha (SNCA) gene responsible for encoding alpha-synuclein, is believed to play a crucial role in the pathogenesis of Parkinson's disease (PD). However, the specific impact of SNCA gene single-nucleotide polymorphisms (SNPs) on brain function in PD remains unclear. Therefore, this cross-sectional retrospective study, particularly through use of imaging analysis, aimed to characterize the relationship between SNCA gene SNPs and spontaneous brain activity in PD in order to enhance our understanding of the mechanisms underlying PD pathogenesis. A total of 63 patients with PD and 73 sex- and age-matched healthy control (HC) participants were recruited from outpatient and inpatient clinics at Fujian Medical University Union Hospital from August 2017 to November 2019, and all underwent a resting-state functional magnetic resonance imaging (rs-fMRI) scanning. All participants were also examined to determine the correlation of different genotypes with regional brain activity measured by rs-fMRI using amplitude of low-frequency fluctuation (ALFF) analysis. Multivariate regression analysis was used to calculate the correlation between the brain function data and clinical features. All rs-fMRI data were analyzed with the SPM12 software and adjusted according to the false discovery rate (FDR) at the cluster level. This study included 63 patients with PD and 73 sex- and age-matched healthy participants were included in the study. The spontaneous brain activity in the right superior cerebellum (Cerebelum_Crus1_R), vermis (Vermis_7), and left supplementary motor area (Supp_Motor_Area_L) of patients in the PD group was weak compared to that in the HC group. The z-score ALFF of left central posterior gyrus was positively correlated with the Mini-Mental State Examination score (r=0.542; P<0.001) in the PD group. For rs11931074, the main genotypic effects were found in the left inferior cerebellum (Cerebellum_9_L) and right anterior cingulate and paracingulate gyri (Cingulum_Ant_R); for rs356219 and rs356165, the main genotypic effects were found in the left caudate nucleus (Caudate_L). An interaction effect of disease with genotype was found in the right inferior parietal gyrus (Parietal_Inf_R) only for rs356219. Our study found a correlation of the SNCA SNPs rs11931074, rs356219, and rs356165 with brain functional alterations in patients with PD. Furthermore, an interaction effect was found in the right inferior parietal gyrus only for rs356219. This study may contribute to furthering the understanding of the influence of SNCA gene SNPs on brain function in patients with PD.

Secondary analysis reveals gut microbiota differences in patients with Parkinson’s disease and/or cognitive impairment

Background: Parkinson’s disease (PD) is a neurodegenerative disorder, and the main clinical characteristics are bradykinesia and muscle stiffness. Cognitive impairment (CI) is a prevalent non-motor manifestation observed in individuals with PD. According to disease severity, it can be divided into PD with mild cognitive impairment (MCI) and PD dementia. CI in PD patients may precede motor symptoms, and the gut microbiota plays an important role in PD pathogenesis. Therefore, gut microbiota may be one of the diagnostic targets for PD-CI. Methods: This study compared the gut microbiota of 43 PD-CI patients [Montreal Cognitive Assessment (MoCA) score &lt; 26] and 38 PD patients without CI (MoCA ≥ 26). Patients’ neuropsychological conditions, depression scale, and brain structure scanned by magnetic resonance imaging (MRI) were also recorded. The fecal metagenomic datasets of patients with PD, PD-CI, and CI only were retrieved from public databases for reanalysis to explore the relationship between PD, CI, and gut microbiota. Results: We found that the cortical thickness and the volume of the hippocampus, gray matter, and thalamus were significantly reduced among patients with PD-CI compared to PD without CI (P &lt; 0.05). Moreover, the gut microbiome in patients with PD-CI had fewer short-chain fatty acid (SCFA) producing bacteria and more pathogenic bacteria. There were also alterations in patterns of metabolic pathway-encoding genes. Additionally, PD affected gut microbiota more than CI. Conclusion: CI may aggravate the severity of PD, but it did not drastically alter subjects’ gut microbiota. This study reveals the relationship between gut microbiota, PD, and CI.

Quantitative systems pharmacology model of α-synuclein pathology in Parkinson's disease-like mouse for investigation of passive immunotherapy mechanisms.

The main pathophysiological hallmark of Parkinson's disease (PD) is the accumulation of aggregated alpha-synuclein (αSyn). Microglial activation is an early event in PD and may play a key role in pathological αSyn aggregation and transmission, as well as in clearance of αSyn and immunotherapy efficacy. Our aim was to investigate how different proposed mechanisms of anti-αSyn immunotherapy may contribute to pathology reduction in various PD-like mouse models. Our mechanistic model of PD pathology in mouse includes αSyn production, aggregation, degradation and distribution in neurons, secretion into interstitial fluid, internalization, and subsequent clearance by neurons and microglia. It describes the influence of neuroinflammation on PD pathogenesis and dopaminergic neurodegeneration. Multiple data from mouse PD models were used for calibration and validation. Simulations of anti-αSyn passive immunotherapy adequately reproduce preclinical data and suggest that (1) immunotherapy is efficient in the reduction of aggregated αSyn in various models of PD-like pathology; (2) prevention of aSyn spread only does not reduce the pathology; (3) a decrease in microglial inflammatory activation and aSyn aggregation may be alternative therapy approaches in PD-like pathology.

Antagonism of β-arrestins in IL-4-driven microglia reactivity via the Samd4/mTOR/OXPHOS axis in Parkinson's disease.

Interleukin-4 (IL-4)-exposed microglia acquire neuroprotective properties, but their functions and regulation in Parkinson's disease (PD) are poorly understood. In this study, we demonstrate that IL-4 enhances anti-inflammatory microglia reactivity, ameliorates the pathological features of PD, and reciprocally affects expression of β-arrestin 1 and β-arrestin 2 in microglia in PD mouse models. We also show that manipulation of two β-arrestins produces contrary effects on the anti-inflammatory states and neuroprotective action of microglia induced by IL-4 in vivo and in vitro. We further find that the functional antagonism of two β-arrestins is mediated through sequential activation of sterile alpha motif domain containing 4 (Samd4), mammalian target of rapamycin (mTOR), and mitochondrial oxidative phosphorylation (OXPHOS). Collectively, these data reveal opposing functions of two closely related β-arrestins in regulating the IL-4-induced microglia reactivity via the Samd4/mTOR/OXPHOS axis in PD mouse models and provide important insights into the pathogenesis and therapeutics of PD.

Genome-wide association study of copy number variations in Parkinson's disease.

Our study investigates the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data, aiming to uncover novel genetic mechanisms and improve the understanding of the role of CNVs in sporadic PD. We applied a sliding window approach to perform CNV-GWAS and conducted genome-wide burden analyses on CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium. We identified 14 genome-wide significant CNV loci associated with PD, including one deletion and 13 duplications. Among these, duplications in 7q22.1, 11q12.3 and 7q33 displayed the highest effect. Two significant duplications overlapped with PD-related genes SNCA and VPS13C, but none overlapped with recent significant SNP-based GWAS findings. Five duplications included genes associated with neurological disease, and four overlapping genes were dosage-sensitive and intolerant to loss-of-function variants. Enriched pathways included neurodegeneration, steroid hormone biosynthesis, and lipid metabolism. In early-onset cases, four loci were significantly associated with EOPD, including three known duplications and one novel deletion in PRKN. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. This is the largest CNV-based GWAS in PD identifying novel CNV regions and confirming the significant CNV burden in EOPD, primarily driven by the PRKN gene, warranting further investigation.

Fibrin-Polycaprolactone Scaffolds for the Differentiation of Human Neural Progenitor Cells into Dopaminergic Neurons.

Parkinson's disease (PD), a progressive central nervous system disorder marked by involuntary movements, poses a significant challenge in neurodegenerative research due to the gradual degeneration of dopaminergic (DA) neurons. Early diagnosis and understanding of PD's pathogenesis could slow disease progression and improve patient management. In vitro modeling with DA neurons derived from human-induced pluripotent stem cell-derived neural progenitor cells (NPCs) offers a promising approach. These neurons can be cultured on electrospun (ES) nanofibrous polycaprolactone (PCL) scaffolds, but PCL's hydrophobic nature limits cell adhesion. We investigated the ability of ES PCL scaffolds coated with hydrophilic extracellular matrix-based biomaterials, including cell basement membrane proteins, Matrigel, and Fibrin, to enhance NPC differentiation into DA neurons. We hypothesized that fibrin-coated scaffolds would maximize differentiation based on fibrin's known benefits in neuronal tissue engineering. The scaffolds both coated and uncoated were characterized using scanning electron microscopy (SEM), transmission electron microscopy, Fourier transform infrared spectroscopy-attenuated total reflectance, and dynamic mechanical analysis to assess their properties. NPCs were seeded on the coated scaffolds, differentiated, and matured into DA neurons. Immunocytochemistry targeting tyrosine hydroxylase (TH) and SEM confirmed DA neuronal differentiation and morphological changes. Electrophysiology via microelectrode array recorded their neuronal firing. Results showed enhanced neurite extension, increased TH expression, and active electrical activity in cells on fibrin-coated scaffolds. Diluted fibrin coatings particularly promoted more pronounced neuronal differentiation and maturation. This study introduces a novel tissue-on-a-chip platform for neurodegenerative disease research using DA neurons.

Unveiling the link: hepatitis C virus and Parkinson’s disease

BackgroundParkinson disease (PD) is one of the disabling neurological disorders. The etiology of Parkinson disease is still unknown. Hepatitis C virus is one of the neurotropic viruses which is incriminated in the pathogenesis of Parkinson disease. Hepatitis C virus might affect the dopaminergic neurons, affecting the advancement of PD.MethodsThis study is observational, cross-sectional study done on 2 phases: one phase on PD patients without history of HCV and another phase on HCV patients with no history of PD. 104 PD patient were tested for HCV antibodies and 40 HCV patients with various grades of liver fibrosis were assessed for early pre-motor symptoms of parkinsonism.ResultsAmong patients with parkinsonism, HCV Abs testing was negative in all the studied patients. On the other hand, chronic HCV group included 40 patients, 27.5% were cirrhotic (11/40). Child C patients showed significantly higher percentages of non-motor parkinsonian symptoms, and regarding the HCV group, the majority (85%) of the patients show cognitive impairment, (27.5%) were at stage 1 of anxious mood, while half (50%) of the patients were at stage 1 of fatigue as evaluated by UPDRS Score. Cirrhosis was a significant factor for having non-motor (early) parkinsonism.ConclusionHere we show that advanced cirrhosis is associated with a variety of neurological symptoms including parkinsonian, which needs awareness for better preventive and therapeutic measures for early treatment of hepatitis avoiding the occurrence of cirrhosis, which can lead to parkinsonism.

RXR nuclear receptor signaling modulates lipid metabolism and triggers lysosomal clearance of alpha-synuclein in neuronal models of synucleinopathy

Disease-modifying strategies for Parkinson disease (PD), the most common synucleinopathy, represent a critical unmet medical need. Accumulation of the neuronal protein alpha-synuclein (αS) and abnormal lipid metabolism have each been implicated in PD pathogenesis. Here, we elucidate how retinoid-X-receptor (RXR) nuclear receptor signaling impacts these two aspects of PD pathogenesis. We find that activated RXR differentially regulates fatty acid desaturases, significantly reducing the transcript levels of the largely brain-specific desaturase SCD5 in human cultured neural cells and PD patient-derived neurons. This was associated with reduced perilipin-2 protein levels in patient neurons, reversal of αS-induced increases in lipid droplet (LD) size, and a reduction of triglyceride levels in human cultured cells. With regard to αS proteostasis, our study reveals that RXR agonism stimulates lysosomal clearance of αS. Our data support the involvement of Polo-like kinase 2 activity and αS S129 phosphorylation in mediating this benefit. The lowering of cellular αS levels was associated with reduced cytotoxicity. Compared to RXR activation, the RXR antagonist HX531 had the opposite effects on LD size, SCD, αS turnover, and cytotoxicity, all supporting pathway specificity. Together, our findings show that RXR-activating ligands can modulate fatty acid metabolism and αS turnover to confer benefit in cellular models of PD, including patient neurons. We offer a new paradigm to investigate nuclear receptor ligands as a promising strategy for PD and related synucleinopathies.

Peripheral Blood Immune Cells from Individuals with Parkinson's Disease or Inflammatory Bowel Disease Share Deficits in Iron Storage and Transport that are Modulated by Non-Steroidal Anti-Inflammatory Drugs.

Parkinson's Disease (PD) is a multisystem disorder in which dysregulated neuroimmune crosstalk and inflammatory relay via the gut-blood-brain axis have been implicated in PD pathogenesis. Although alterations in circulating inflammatory cytokines and reactive oxygen species (ROS) have been associated with PD, no biomarkers have been identified that predict clinical progression or disease outcome. Gastrointestinal (GI) dysfunction, which involves perturbation of the underlying immune system, is an early and often-overlooked symptom that affects up to 80% of individuals living with PD. Interestingly, 50-70% of individuals with inflammatory bowel disease (IBD), a GI condition that has been epidemiologically linked to PD, display chronic illness-induced anemia - which drives toxic accumulation of iron in the gut. Ferroptotic (or iron loaded) cells have small and dysmorphic mitochondria-suggesting that mitochondrial dysfunction is a consequence of iron accumulation. In pro-inflammatory environments, iron accumulates in immune cells, suggesting a possible connection and/or synergy between iron dysregulation and immune cell dysfunction. Peripheral blood mononuclear cells (PBMCs) recapitulate certain PD-associated neuropathological and inflammatory signatures and can act as communicating messengers in the gut-brain axis. Additionally, this communication can be modulated by several environmental factors; specifically, our data further support existing literature demonstrating a role for non-steroidal anti-inflammatory drugs (NSAIDs) in modulating immune transcriptional states in inflamed individuals. A mechanism linking chronic gut inflammation to iron dysregulation and mitochondrial function within peripheral immune cells has yet to be identified in conferring risk for PD. To that end, we isolated PBMCs and simultaneously evaluated their directed transcriptome and bioenergetic status, to investigate if iron dysregulation and mitochondrial sensitization are linked in individuals living with PD or IBD because of chronic underlying remittent immune activation. We have identified shared features of peripheral inflammation and immunometabolism in individuals living with IBD or PD that may contribute to the epidemiological association reported between IBD and risk for PD.