Occurrence Of Parkinson's Disease Research Articles

The TLR4/NF-κB/NLRP3 and Nrf2/HO-1 pathways mediate the neuroprotective effects of alkaloids extracted from Uncaria rhynchophylla in Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder with limited therapeutic options available. Neuroinflammation plays an important role in the occurrence and development of PD. Alkaloids extracted from Uncaria rhynchophylla (URA), have emerged as a potential neuroprotective agent because of its anti-inflammatory and anti-oxidant properties. Nevertheless, the underlying mechanism by which URA exerts neuroprotective effects in PD remains obscure. The main aim of this study was to investigate the neuroprotective effects and underlying mechanism of URA in the treatment of PD through in vivo and in vitro models, focusing on the neuroinflammation and oxidative stress pathways. The protective effects of URA against PD were evaluated by neurobehavioral tests, immunohistochemistry, serum biochemical assays, and real-time quantitative polymerase chain reaction in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. The role of the TLR4/NF-κB/NLRP3 pathway and the Nrf2/HO-1 pathway in URA-mediated effects was examined in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a microglia-neuron coculture system. URA significantly alleviated motor deficits and dopaminergic neurotoxicity, and reversed the abnormal secretion of inflammatory and oxidative stress factors in the serum of MPTP-induced mice. URA suppressed the gene expression of Toll-like receptor 4 (TLR4), NOD-like receptor protein 3, and cyclooxygenase 2 (COX2) in the striatum of PD mice. Further studies indicated that URA inhibited activation of the TLR4/NF-κB/NLRP3 pathway and enhanced activation of the Nrf2/HO-1 pathway, reduced reactive oxygen species (ROS) production, and reversed the secretion of inflammatory mediators in LPS-stimulated BV-2 microglial cells, thereby alleviating neuroinflammatory damage to SH-SY5Y neuronal cells. URA exerted neuroprotective effects against PD mainly by the inhibition of the TLR4/NF-κB/NLRP3 pathway and activation of the Nrf2/HO-1 antioxidant pathway, highlighting URA as a promising candidate for PD treatment.

Elucidating the association between direct-acting antivirals and Parkinson's disease in patients with hepatitis C virus infection

BackgroundSome epidemiological studies have found an increased association between Parkinson's disease (PD) and chronic hepatitis C virus (HCV) infection. Although a few studies have also found a decreased risk of PD with interferon-α therapy, the effect of direct-acting antivirals (DAAs) on Parkinson's disease remains unclear. The current study seeks to assess and elucidate the association between DAAs and PD in patients newly diagnosed with chronic HCV infection. MethodsWe conducted a retrospective cohort study of patients ≥18 years diagnosed with HCV using MarketScan Commercial and Medicare Supplemental database (2012–2019). Follow-up started with the initiation of DAA (or randomly assigned date for the non-DAA group) and ended at occurrence of PD, disenrollment, or end of the study period. A multivariable Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals. ResultsWe identified 48,356 patients diagnosed with HCV. The mean follow-up time of the cohort was 1.31 years. The incidence rate of PD was 53 per 100,000 person-years for the DAA group and 48 per 100,000 person-years for the non-DAA group. The adjusted HR was 1.24 (95% CI = 0.56–2.73). Results were consistent across sensitivity and subgroup analyses. ConclusionThis study did not find an association between DAAs and PD among patients with HCV infection.

Ameliorating Mitochondrial Dysfunction for the Therapy of Parkinson's Disease.

Parkinson's disease (PD) is currently the second most incurable central neurodegenerative disease resulting from various pathogenesis. As the "energy factory" of cells, mitochondria play an extremely important role in supporting neuronal signal transmission and other physiological activities. Mitochondrial dysfunction can cause and accelerate the occurrence and progression of PD. How to effectively prevent and suppress mitochondrial disorders is a key strategy for the treatment of PD from the root. Therefore, the emerging mitochondria-targeted therapy has attracted considerable interest. Herein, the relationship between mitochondrial dysfunction and PD, the causes and results of mitochondrial dysfunction, and major strategies for ameliorating mitochondrial dysfunction to treat PD are systematically reviewed. The study also prospects the main challenges for the treatmentofPD.

Dietary vitamin E intake and risk of Parkinson's disease: a cross-sectional study.

Current evidence on the association between dietary vitamin E intake and the risk of Parkinson's disease (PD) is limited. The aim of the study was to explore the association of dietary vitamin E intake with PD in the United States among adults over 40 years. We conducted a cross-sectional study with data collected from National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018. A total of the sample of 13,340 participants were included. To identify the different characteristics of the participants, we utilized propensity score matching (PSM) to reduce the effects of selection bias and confounding variables. Weighted univariate and multivariable logistic regression were used to examine the association between dietary vitamin E intake and PD before and after matching. Then, restricted cubic spline (RCS) was used to visually describe the possible non-linear relationships. Finally, we employed the subgroup analysis to further investigate the relationship between dietary vitamin E intake and PD. According to the weighted univariate and multivariable logistic regression analysis, vitamin E intake was inversely associated with the risk of PD before and after matching. The results of RCS analysis revealed no non-linear inverse relationship between vitamin E intake and PD before and after matching. The subgroup analysis showed that age may influence the negative association between vitamin E and PD (P < 0.05 for interaction). Among participants over 40 years of age, vitamin E intake was negatively associated with the risk of PD. Our data may support the supplementation of vitamin E to be used as an intervention strategy for the occurrence of PD.

Hair color, family history of melanoma, and the risk of Parkinson's disease: An analysis update

BackgroundA shared biological component between melanoma and Parkinson's disease (PD) has been suggested. Yet, epidemiological evidence is scarce. ObjectiveTo examine the association of hair color and family history of melanoma, two strong predictors of melanoma risk, with the occurrence of PD. MethodsWe followed 131,342 women and men for ∼30 years for the development of PD. We calculated the cumulative incidence of PD from ages 40 to 90 according to hair color, and estimated the hazard ratio of PD according to hair color and family history of melanoma. ResultsHair color was not strongly associated with the risk of PD, especially at advanced ages. In contrast, individuals with a family history of melanoma had a 1.4-fold higher risk of PD compared to those without a history. ConclusionsOur results support the hypothesis of a shared biological component between PD and melanoma. Both pigmentary and non-pigmentary pathways may play a role.

Effects of electroacupuncture on the intestinal thioredoxin interaction protein/Nod-like receptor 3 signaling pathway in mice with Parkinson's disease.

To observe the effects of electroacupuncture (EA) at "Fengfu" (GV16), "Taichong" (LR3) and "Zusanli" (ST36) on α-synuclein (α-syn), Occludin, Claudin-1, thioredoxin interaction protein (TXNIP) and Nod-like receptor 3 (NLRP3) in Parkinson's disease (PD) mice, so as to investigate the mechanisms of EA on intestinal barrier function and inflammation in PD mice. Thirty six C57BL/6 mice were randomly divided into control, model and EA groups, with 12 mice in each group. PD mice model was induced by rotenone intragastric administration for 28 days. Mice in the EA group were treated with EA (2 Hz, 1 mA) at GV16, LR3 and ST36 for 30 min, once a day for 14 days. The behavioral scores were observed. The total distance of autonomic movement was measured by open field test. The expression level of α-syn in substantia nigra and colon tissue was determined by immunohistochemistry. The colonic morphology and goblet cell distribution were observed by Alcian blue staining. The expression levels of Occludin, Claudin-1, TXNIP and NLRP3 mRNA in colon tissue were detected by real-time fluorescence quantitative PCR. Compared with the control group, the behavioral scores of rats were increased (P<0.01)；the total distance of autonomous movement was decreased (P<0.01)；the positive expression level of α-syn in the substantia nigra and colon was increased (P<0.01)；the goblet cells and crypts in colon tissue were reduced, and the muscular layer was thinner；the expression levels of Occludin and Claudin-1 mRNAs in colon tissue were decreased (P<0.01) while TXNIP and NLRP3 mRNAs were increased (P<0.01) in the model group. Compared with the model group, the surface villi of colon tissue was more complete, the goblet cells and crypts were increased, and the muscular layer was thickened；the other indexes were reversed (P<0.01, P<0.05) in the EA group. EA at GV16, LR3 and ST36 can reduce the abnormal accumulation of α-syn in the substania nigra and colon tissue of PD mice, alleviate the damage of intestinal barrier, regulate TXNIP/NLRP3 signaling pathway, so as to delay the occurrence and development of PD.

The function of astrocytes and their role in neurological diseases.

Astrocytes have countless links with neurons. Previously, astrocytes were only considered a scaffold of neurons; in fact, astrocytes perform a variety of functions, including providing support for neuronal structures and energy metabolism, offering isolation and protection and influencing the formation, function and elimination of synapses. Because of these functions, astrocytes play an critical role in central nervous system (CNS) diseases. The regulation of the secretiory factors, receptors, channels and pathways of astrocytes can effectively inhibit the occurrence and development of CNS diseases, such as neuromyelitis optica (NMO), multiple sclerosis, Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The expression of aquaporin 4 in AS is directly related to NMO and indirectly involved in the clearance of Aβ and tau proteins in AD. Connexin 43 has a bidirectional effect on glutamate diffusion at different stages of stroke. Interestingly, astrocytes reduce the occurrence of PD through multiple effects such as secretion of related factors, mitochondrial autophagy and aquaporin 4. Therefore, this review is focused on the structure and function of astrocytes and the correlation between astrocytes and CNS diseases and drug treatment to explore the new functions of astrocytes with the astrocytes as the target. This, in turn, would provide a reference for the development of new drugs to protect neurons and promote the recovery of nerve function.

Transcriptome sequencing of circular RNA reveals the involvement of hsa-SCMH1_0001 in the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Exosomes are endosome-derived extracellular vesicles that can take part in intercellular communication. Circular RNAs (circRNAs) are noncoding RNAs characterized by covalently closed-loop structures, which perform a crucial function in many diseases. To clarify the expression and function of exosomal circRNSs of PD patients and look for circRNAs that might be related to the pathogenesis of PD. We examined circRNA and mRNA expression profiles in peripheral exosomes from PD patients (n = 23) and healthy controls (n = 15) using next-generation sequencing (NGS) technology, functional annotation, and quantitative polymerase chain reaction. Correlation analysis was performed between the expression levels of the circRNAs and the clinical characteristics of PD patients. The binding miRNAs and target genes were predicted using TargetScanHuman, miRDB, and miRTarBase. The predicted target genes were compared with the differentially expressed mRNAs in sequencing results. According to the NGS, 62 upregulated and 37 downregulated circRNAs in the PD group were screened out. Correlation analysis revealed that hsa-SCMH1_0001 has strong clinical relevance. We identified 17 potential binding miRNAs of hsa-SCMH1_0001 with 149 potential target genes. ARID1A and C1orf115 belong to the intersection of the predicted target genes and the differentially expressed mRNAs obtained by sequencing. This study suggested that hsa-SCMH1_0001 and its target genes ARID1A and C1orf115 are downregulated in PD patients and may be involved in the occurrence of PD.

Wuzi Yanzong Pill relieves MPTP-induced motor dysfunction and neuron loss by inhibiting NLRP3 inflammasome-mediated neuroinflammation.

Parkinson disease (PD) is an age-related neurodegenerative disease, which is associated with the loss of dopaminergic neurons (DA neurons) in the substantia nigra pars compacta (SNpc), and neuroinflammation may lead to the occurrence of PD. Wuzi Yanzong Pill (WYP) has demonstrated neuroprotective and anti-inflammatory properties, but its molecular mechanism of action is still unclear. In this study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice and LPS-mediated BV2 microglia to explore WYP intervention, anti-inflammatory effect and molecular mechanism in vivo and in vitro. The results showed that oral administration of WYP in MPTP-induced PD mice for 2 weeks ameliorated abnormal motor dysfunction, attenuated the loss of TH + neurons in SNpc, protected dopaminergic neurons, and inhibited the activation of microglia in MPTP-induced PD mice and LPS-stimulated BV2 cell. Meanwhile, WYP intervention inhibited the expression of IL-6, TNF-α, Pro-IL-1β, IL-1β, Pro-IL-18, IL-18 and enhanced the expression of IL-10 in the SNpc of PD mice. Simultaneously, WYP intervention inhibited the expression of NLRP3 inflammasome, accompanied by the decrease of the TLR4/MyD88/NF-κB pathway. However, the exact target and interaction of WYP on NLRP3 inflammasome and TLR4/MyD88/NF-κB pathway still needs to be further investigated.

Identification of Cuproptosis Clusters and Integrative Analyses in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease; it mainly occurs in the elderly population. Cuproptosis is a newly discovered form of regulated cell death involved in the progression of various diseases. Combining multiple GEO datasets, we analyzed the expression profile and immunity of cuproptosis-related genes (CRGs) in PD. Dysregulated CRGs and differential immune responses were identified between PD and non-PD substantia nigra. Two CRG clusters were defined in PD. Immune analysis suggested that CRG cluster 1 was characterized by a high immune response. The enrichment analysis showed that CRG cluster 1 was significantly enriched in immune activation pathways, such as the Notch pathway and the JAK-STAT pathway. KIAA0319, AGTR1, and SLC18A2 were selected as core genes based on the LASSO analysis. We built a nomogram that can predict the occurrence of PD based on the core genes. Further analysis found that the core genes were significantly correlated with tyrosine hydroxylase activity. This study systematically evaluated the relationship between cuproptosis and PD and established a predictive model for assessing the risk of cuproptosis subtypes and the outcome of PD patients. This study provides a new understanding of PD-related molecular mechanisms and provides new insights into the treatment of PD.

The Role of Endophilin A1 in Lipopolysaccharide-Induced Parkinson's Disease Model Mice.

Endophilin A1 (EPA1) is encoded by the SH3GL2 gene, and SH3GL2 was designated as a Parkinson's disease (PD) risk locus by genome-wide association analysis, suggesting that EPA1 may be involved in the occurrence and development of PD. To investigate the role of EPA1 in lipopolysaccharide (LPS)-induced PD model mice. The mice PD model was prepared by injecting LPS into the substantia nigra (SN), and the changes in the behavioral data of mice in each group were observed. The damage of dopaminergic neurons, activation of microglia, and reactive oxygen species (ROS) generation were detected by immunofluorescence method; calcium ion concentration was detected by calcium content detection kit; EPA1 and inflammation and its related indicators were detected by western blot method. EPA1 knockdown was performed by an adeno-associated virus vector containing EPA1-shRNA-eGFP infusion. LPS-induced PD model mice developed behavioral dysfunction, SN dopaminergic nerve damage, significantly increased calcium ion, calpain 1, and ROS production, activated NLRP1 inflammasome and promoted pro-inflammatory cell release, and SN EPA1 knockdown improves behavioral disorders, alleviates dopaminergic neuron damage, reduces calcium, calpain 1, ROS generation, and blocks NLRP1 inflammasome-driven inflammatory responses. The expression of EPA1 in the SN of LPS-induced PD model mice was increased, and it played a role in promoting the occurrence and development of PD. EPA1 knockdown inhibited the NLRP1 inflammasome activation, decreased the release of inflammatory factors and ROS generation, and alleviated dopaminergic neuron damage. This indicated that EPA1 may participating in the occurrence and development of PD.

Increased risk of Parkinson's disease among patients with age-related macular degeneration and visual disability: A nationwide cohort study.

The association between Parkinson's disease (PD) and age-related macular degeneration (AMD) has been shown in previous reports. However, the association between the severity of AMD and PD development is unknown. We aimed to evaluate the association of AMD with/without visual disability (VD) with the risk of PD occurrence using the National Health Insurance data in South Korea. A total of 4,205,520 individuals, older than or equal to 50 years and without a previous diagnosis of PD, participated in the Korean National Health Screening Program in 2009. AMD was verified using diagnostic codes, and participants with VD were defined as those with loss of vision or visual field defect as certified by the Korean government. The participants were followed up until 31 December, 2019, and incident cases of PD were identified using registered diagnostic codes. The hazard ratio was calculated for groups (control and AMD with/without visual disability) using multivariable adjusted Cox regression analysis. In total, 37,507 participants (0.89%) were diagnosed with PD. Among individuals with AMD, the risk of PD development was higher in individuals with VD (aHR 1.35, 95% CI 1.09-1.67) than those without (aHR 1.22, 95% CI 1.15-1.30) compared with controls. Additionally, an increased risk of PD was observed in individuals with AMD compared with controls, regardless of the presence of VD (aHR 1.23, 95% CI 1.16-1.31). VD in AMD was associated with the development of PD. This suggests that neurodegeneration in PD and AMD may have common pathways.

DPP-4 inhibitors and type 2 diabetes mellitus in Parkinson's disease: a mutual relationship.

Parkinson's disease (PD) usually occurs due to the degeneration of dopaminergic neurons in the substantia nigra (SN). Management of PD is restricted to symptomatic improvement. Consequently, a novel treatment for managing motor and non-motor symptoms in PD is necessary. Abundant findings support the protection of dipeptidyl peptidase 4 (DPP-4) inhibitors in PD. Consequently, this study aims to reveal the mechanism of DPP-4 inhibitors in managing PD. DPP-4 inhibitors are oral anti-diabetic agents approved for managing type 2 diabetes mellitus (T2DM). T2DM is linked with an increased chance of the occurrence of PD. Extended usage of DPP-4 inhibitors in T2DM patients may attenuate the development of PD by inhibiting inflammatory and apoptotic pathways. Thus, DPP-4 inhibitors like sitagliptin could be a promising treatment against PD neuropathology via anti-inflammatory, antioxidant, and anti-apoptotic impacts. DPP-4 inhibitors, by increasing endogenous GLP-1, can also reduce memory impairment in PD. In conclusion, the direct effects of DPP-4 inhibitors or indirect effects through increasing circulating GLP-1 levels could be an effective therapeutic strategy in treating PD patients through modulation of neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurogenesis.

Synergistic effects of lipopolysaccharide and rotenone on dopamine neuronal damage in rats.

The etiology of Parkinson's disease (PD) is still unknown. Until now, oxidative stress and neuroinflammation play a crucial role in the pathogenesis of PD. However, the specific synergistic role of oxidative stress and neuroinflammation in the occurrence and development of PD remains unclear. The changes in motor behavior, dopamine (DA) neurons quantification and their mitochondrial respiratory chain, glial cells activation and secreted cytokines, Nrf2 signaling pathway, and redox balance in the brain of rats were evaluated. Lipopolysaccharide (LPS)-induced neuroinflammation and rotenone (ROT)-induced oxidative stress synergistically aggravated motor dysfunction, DA neuron damage, activation of glial cells, and release of related mediators, activation of Nrf2 signaling and destruction of oxidative balance. In addition, further studies indicated that after ROT-induced oxidative stress caused direct damage to DA neurons, LPS-induced inflammatory effects had stronger promoting neurotoxic effects on the above aspects. Neuroinflammation and oxidative stress synergistically aggravated DA neuronal loss. Furtherly, oxidative stress followed by neuroinflammation caused more DA neuronal loss than neuroinflammation followed by oxidative stress.

Essential tremor-Parkinson's disease syndrome: clinical characteristics and subtypes using cluster analysis.

Essential tremor (ET) and Parkinson's disease (PD) are common movement disorders. ET-PD syndrome is characterized by the occurrence of PD in patients with a previous history of ET, which may be an independent phenotype distinct from PD. This study aims to identify clinical characteristics and subtypes in ET-PD. A total of 93 newly diagnosed ET-PD patients and 93 newly diagnosed PD patients matched for age, sex, education, and disease duration of PD were selected using propensity score matching analysis. The K-means cluster analysis was performed for 11 variables derived from the ET-PD group, and cluster profiles were established through statistical analysis of demographic and clinical variables. The ET-PD group consisted of a high number of patients with a family history of ET exhibiting evident tremor with milder hypokinesia and postural instability symptoms, as compared to the PD group. Through the cluster analysis, two clusters of ET-PD patients were identified. The ET-PD cluster 1 ( n = 34) had a shorter ET duration before PD onset, lower number of patients with a family history of ET, higher unified PD rating scale instability scores, higher non-motor symptoms scores (non-motor symptoms scale D1 scores, Hamilton depression scale scores, Hamilton anxiety scale scores, and PD sleep scale-2 scores), and higher Chinese version of the PD questionnaire-39 scores relative to the ET-PD cluster 2 ( n = 59). ET-PD patients had significantly different characteristics for motor symptoms as compared to PD patients, and may be distinctly divided into two clinical subtypes, namely, the ET-PD complex type and the ET-PD simple type.

Relationship Between Annual Airborne Pollen Levels and Occurrence of Parkinson Disease, Amyotrophic Lateral Sclerosis, Myasthenia Gravis, Multiple Sclerosis, Spinocerebellar Degeneration, Huntington’s Disease, Shy-Drager Syndrome, Moyamoya Disease and Creutzfeldt- Jakob Disease Based on the National Registry Database of Specific Intractable Disease in Japan, 1974-2014: A Retrospective Study

Background: In Japan, pollen counts increased between 1977 and 1987, including three peaks (1978- 1980, 1982, 1984-1986) coinciding with triphasic Kawasaki disease (KD) outbreaks. Epidemiological findings have been then extensively accumulated that KD and related specific intractable diseases such as systemic vasculitis, collagen diseases, inflammatory bowel diseases, idiopathic dilated cardiomyopathy and further various cancers may be correlated to pollen exposure (PE). Methods and results: To elucidate the effects of PE on outbreaks of neurological intractable diseases (NIDs), we evaluated the annual occurrence of disorders in relation to pollen counts using data from a national database. Specifically, we evaluated the occurrence of Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Myasthenia Gravis (MG), multiple sclerosis (MS), spinocerebellar degeneration (SCD), Huntington’s disease (HUNTG), Shy-Drager syndrome, moyamoya disease and CreutzfeldtJakob disease (CJD). During 1975–2014, the 1984-86 peak of pollen scatter was the earliest big peak with which simultaneous increase in occurrence of PD, ALS, MG, MS, SCD and HUNTG coincided. Furthermore, simultaneous outbreaks of each NID coincided with subsequent ten peaks of pollen scatter till 2014. Our results showed statistically significant correlations for PD, ALS, MG, MS and SCD between the annual number of newly registered patients (nRPs) in the patient-registry year and annual pollen levels in the same patient-registry year. Significant correlations were also shown between the number of nRPs in the patient-registry year and annual pollen levels measured 3 years (PD), 6 years (PD, MG, MS, MMD), 9 years (PD, MS, MMD, CJD), 14 years (PD, CJD), and 16 years MG, MS, HUNTG and MMD before the patient-registry year. Conclusion: We assume that cumulative effects of PE during a decade or more before the diagnosis of NIDs might possibly trigger onset of NIDs when cumulative effects of PE as environmental stress overwhelmed immunoreactive threshold.

PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats

Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease (PD). However, the mechanisms underlying this association remain unclear. In the present study, we found that high glucose (HG) levels in the cerebrospinal fluid (CSF) of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine (6-OHDA) on the development of motor disorders, and the damage to the nigrostriatal dopaminergic neuronal pathway. In vitro, HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor (NGF) (NGF-PC12). Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle (TCA cycle) activity, which was closely related to abnormal mitochondrial fusion, thus resulting in mitochondrial loss. Interestingly, HG-induced upregulation of pyruvate kinase M2 (PKM2) combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells. In addition, we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HG+6-OHDA. Furthermore, we found that shikonin (SK), an inhibitor of PKM2, restored the mitochondrial number, promoted TCA cycle activity, reversed hyperglycolysis, enhanced the tolerance of cultured neurons to 6-OHDA, and reduced the risk of PD in diabetic rats. Overall, our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2, leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA. Thus, the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.

Clinical and Genetic Features of Multiplex Families with Multiple System Atrophy and Parkinson's Disease.

While multiple system atrophy (MSA) has been considered a sporadic disease, there were previously reported multiplex families with MSA. Furthermore, several families with multiple patients with MSA and Parkinson's disease (PD) have been reported. As genetic risk factors for MSA, functionally impaired variants in COQ2 and Gaucher-disease-causing GBA variants have been reported. While it has been established that GBA variants are associated with PD, COQ2 may also be associated with PD. In 672 patients with MSA, we identified 12 multiplex families of patients with MSA and PD in first-degree relatives. We conducted a detailed analysis of the clinical presentations of these patients and genetic analyses of GBA and COQ2. In the multiplex families, a patient with MSA with predominant parkinsonism (MSA-P) was observed in nine families, while a patient with MSA cerebellar subtype (MSA-C) was observed in three families. Six families had siblings with MSA and PD, five families had a parent-offspring pair with MSA and PD, and in one family, a sibling and a parent of an MSA patient had PD. In genetic analyses of these patients, GBA variants were identified in one of the 12 MSA patients and two of the seven PD patients. Functionally impaired variants of COQ2 were identified in two of the 12 MSA patients and not identified in the seven PD patients. This study further emphasizes the occurrence of MSA and PD in first-degree relatives, raising the possibility that a common genetic basis underlies MSA and PD. Even though variants of COQ2 and GBA were identified in some patients in multiplex families with MSA and PD, it is necessary to further explore as yet unidentified genetic risk factors shared by MSA and PD.

Influence of heavy metals in Parkinson's disease: an overview.

Parkinson's disease (PD) is an ageing disorder with deterioration of dopamine neurons which leads to motor complications like tremor, stiffness, slow movement and postural disturbances. In PD, both genetics as well as environmental factors both play a major role in causing the pathogenesis. Though there are surfeit of risk factors involved in PD occurrence, till now there is lack of an exact causative agent as a risk for PD with confirmative findings. The role of heavy metals reported to be a significant factor in PD pathogenesis. Heavy metal functions in cell maintenance but growing pieces of evidences reported to cause dyshomeostasis with increased PD rate. Metals disturb the molecular processes and results in oxidative stress, DNA damage, mitochondrial dysfunction, and apoptosis. The present review elucidates the role of cobalt, nickel, mercury, chromium, thallium metals in α-synuclein aggregation and its involvement in blood brain barrier flux. Also, the review explains the plausible role of aforementioned metals with a mechanistic approach and therapeutic recommendations in PD.

Identification of alpha‐Synuclein Disaggregator from Camellia sp. Insight of Molecular Docking and Molecular Dynamics Simulations

AbstractMisfolded protein formation and aggregation are the central hallmarks for various neurodegenerative disorders. When it comes to Parkinson's disease (PD), alpha‐synuclein (α‐syn) is the culprit protein. The presence of α‐syn protein in lewy bodies and lewy neurites confirmed its presence in the occurrence of PD. The protein is natively present in the soluble monomeric forms, but certain factors such as oxidative stress convert the structure into insoluble oligomeric formats. This study focuses on the inhibitory effects of various antioxidant compounds on α‐syn oligomerization. We had collected the list of compounds present in the Camellia sp. plant. Using a computational approach, we found the potential interaction sites between the antioxidant compounds and α‐syn using a computational approach. Molecular docking and simulation studies suggest that the compound Theaflavin‐3‐3‐digallate shows best interactions with −7.1 kcal/mol and can reduce the alpha‐sheet structure of α‐syn structure to loop region.