Etiopathogenesis Of Parkinson's Disease Research Articles

Incretin Mimetics Restore the ER-Mitochondrial Axis and Switch Cell Fate Towards Survival in LUHMES Dopaminergic-Like Neurons: Implications for Novel Therapeutic Strategies in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that afflicts more than 10 million people worldwide. Available therapeutic interventions do not stop disease progression. The etiopathogenesis of PD includes unbalanced calcium dynamics and chronic dysfunction of the axis of the endoplasmic reticulum (ER) and mitochondria that all can gradually favor protein aggregation and dopaminergic degeneration. In Lund Human Mesencephalic (LUHMES) dopaminergic-like neurons, we tested novel incretin mimetics under conditions of persistent, calcium-dependent ER stress. We assessed the pharmacological effects of Liraglutide-a glucagon-like peptide-1 (GLP-1) analog-and the dual incretin GLP-1/GIP agonist DA3-CH in the unfolded protein response (UPR), cell bioenergetics, mitochondrial biogenesis, macroautophagy, and intracellular signaling for cell fate in terminally differentiated LUHMES cells. Cells were co-stressed with the sarcoplasmic reticulum calcium ATPase (SERCA) inhibitor, thapsigargin. We report that Liraglutide and DA3-CH analogs rescue the arrested oxidative phosphorylation and glycolysis. They mitigate the suppressed mitochondrial biogenesis and hyper-polarization of the mitochondrial membrane, all to re-establish normalcy of mitochondrial function under conditions of chronic ER stress. These effects correlate with a resolution of the UPR and the deficiency of components for autophagosome formation to ultimately halt the excessive synaptic and neuronal death. Notably, the dual incretin displayed a superior anti-apoptotic effect, when compared to Liraglutide. The results confirm the protective effects of incretin signaling in ER and mitochondrial stress for neuronal degeneration management and further explain the incretin-derived effects observed in PD patients.

Serum salusin-α and -β levels in patients with parkinson's disease.

The etiology of Parkinson's disease (PD) is not well known and there is increasing evidence that oxidative stress also plays an important role in its pathogenesis. Salusins alpha (salusin-α) and beta (salusin-β) affect the central nervous system, vasculature, and kidneys to increase the inflammatory response in endothelial cells, stimulate oxidative stress, and increase monocyte-endothelial adhesion. Neuroinflammation and oxidative stress play roles in the etiopathogenesis of PD. To investigate whether salusin-α and -β are related to PD and whether they are correlated with the development of atherosclerosis, body mass index, disease duration, and the Parkinson's Hoehn and Yahr stage. The low-density lipoprotein cholesterol (LDL-C), total cholesterol, and salusin-β levels were significantly lower and age was significantly higher in Parkinson patients compared to healthy controls (ρ < 0.005). We found a negative linear correlation between salusin-β and the Hoehn and Yahr stage (ρ < 0.001, r = -0.515) in the patients. There was a relationship between salusin-β and PD and a correlation between the salusin-β levels and Parkinson's stage. A possible underlying disease mechanism is an increase in oxidative stress and decrease in neuroprotective effects due to low salusin-β levels. Therefore, the effects of salusin-β in treating Parkinson disease should be evaluated. Further studies are needed to understand the effects of salusin-β treatment on preventing or slowing the course of PD.

Thioredoxin-1 inhibits the activation of IRE1 by targeting Hsp90/p-Cdc37 chaperone complex in Parkinson disease.

Endoplasmic reticulum stress is implicated in the etiopathogenesis of Parkinson disease (PD). Our previous study has revealed that thioredoxin-1 (Trx-1) attenuated IRE1 activation in 1-methyl-4-phenylpyridinium ion (MPP+)/1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models. However, its exact mechanism has been largely unclear. In this research, it was reported for the first time that the protein levels of heat shock protein 90 (Hsp90) and phosphorylated cell division cycle 37 (p-Cdc37) were significantly decreased and the interaction of Hsp90/p-Cdc37 complex with IRE1 was disturbed in MPP+/MPTP-induced PD models. Trx-1 overexpression reversed the expression of Hsp90 and p-Cdc37 in cultured cells and the substantia nigra pars compacta of mice. More importantly, Trx-1 overexpression enhanced the interaction of Hsp90/p-Cdc37 complex with IRE1. In conclusion, our data demonstrated that Trx-1 inhibited IRE1 activation in PD by elevating the expression of Hsp90 and p-Cdc37 and strengthening the interaction of Hsp90/p-Cdc37 complex and IRE1.

Tannic Acid Mitigates Rotenone-Induced Dopaminergic Neurodegeneration by Inhibiting Inflammation, Oxidative Stress, Apoptosis, and Glutamate Toxicity in Rats.

Parkinson's disease (PD), a movement disorder, is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. The etiopathogenesis of PD involves increased oxidative stress, augmented inflammation, impaired autophagy, accumulation of α-synuclein, and α-Glutamate neurotoxicity. The treatment of PD is limited and there is a lack of agents to prevent the disease/delay its progression and inhibit the onset of pathogenic events. Many agents of natural and synthetic origin have been investigated employing experimental models of PD, mimicking human PD. In the present study, we assessed the effect of tannic acid (TA) in a rodent model of PD induced by rotenone (ROT), a pesticide and an environmental toxin of natural origin reported to cause PD in agricultural workers and farmers. Rotenone (2.5 mg/kg/day, i.p.) was administered for 28 days, and TA (50 mg/kg, orally) was administered 30 min before ROT injections. The study results showed an increase in oxidative stress, as evidenced by the depletion of endogenous antioxidants and enhanced formation of lipid peroxidation products, along with the onset of inflammation following a rise in inflammatory mediators and proinflammatory cytokines. ROT injections have also augmented apoptosis, impaired autophagy, promoted synaptic loss, and perturbed α-Glutamate hyperpolarization in rats. ROT injections also induced the loss of dopaminergic neurons subsequent to the activation of microglia and astrocytes. However, TA treatment was observed to reduce lipid peroxidation, prevent loss of endogenous antioxidants, and inhibit the release and synthesis of proinflammatory cytokines, in addition to the favorable modulation of apoptosis and autophagic pathways. Treatment with TA also attenuated the activation of microglia and astrocytes along with preservation of dopaminergic neurons following reduced loss of dopaminergic neurodegeneration and inhibition of synaptic loss and α-Glutamate cytotoxicity. The effects of TA in ROT-induced PD were attributed to the antioxidant, anti-inflammatory, antiapoptotic, and neurogenesis properties. Based on the present study findings, it can be concluded that TA may be a promising novel therapeutic candidate for pharmaceutical as well as nutraceutical development owing to its neuroprotective properties in PD. Further regulatory toxicology and translational studies are suggested for future clinical usage in PD.

SUN11602, a novel bFGF mimetic, exerts neuroprotective effects in Parkinson's disease

Parkinson's disease (PD) is the second most frequent neurodegenerative disease, with a large prevalence in industrialized countries. The etiopathogenesis of PD is multifactorial and not yet fully known, however, in the last few decades, scientific world advised the establishment of a neuroinflammatory state among the possible risk factors. In this field, basic fibroblast growth factor/fibroblast growth factor receptor 1 (bFGF/FGFR1) could be a promising way to treat CNS‐mediated inflammation; however, the use of bFGF as a therapeutic agent is limited by its side effects.The novel synthetic compound SUN11602 exhibited neuroprotective activities like bFGF, but demonstrating greater safety, thus constituting a potential candidate for the treatment of neurodegenerative diseases including PD. In this perspective, this study aimed to evaluate the effect of SUN11602 administration in a murine model of MPTP‐induced PD. PD was induced by intraperitoneal injection of MPTP (80 mg/kg). SUN11602 (1, 2.5, and 5 mg/kg) was administered daily by oral gavage starting from 24 hours after the first administration of MPTP, mice were sacrificed 7 days after MPTP induction. The results obtained showed that SUN11602 administration significantly reduced the alteration of PD hallmarks, attenuating the neuroinflammatory state via modulation of glial activation, NF‐kB pathway and cytokine overexpression. Furthermore, we demonstrated that SUN11602 treatment rebalanced Ca2+ overload in neurons by regulating Ca2+‐binding proteins, inhibiting the apoptotic cascade. Therefore, considering these findings, SUN11602 could be considered a valuable pharmacological strategy for PD.

Parkinson's disease is an autoimmune disease: A reappraisal.

Parkinson's disease (PD) is a common, age-related, neurodegenerative disorder characterized by motor deficits and a cognitive decline. In the large majority of cases, it is associated with cytoplasmic aggregation of α-synuclein/SNCA and the formation of Lewy bodies in the dopamine neurons in the substantia nigra pars compacta. The etiopathogenesis of PD remains poorly understood. The disease results from an interplay of genetic and environmental factors, including pharmacological molecules, which destroy dopaminergic neurons. Recently, several notable data have highlighted various immune alterations underlying that PD is associated to autoimmune features and could be considered as an autoimmune disease. In this short article, we briefly review key elements participating to this emerging viewpoint.

Biofluid Markers for Prodromal Parkinson's Disease: Evidence From a Catecholaminergic Perspective.

Parkinson's disease (PD) is the most frequent of all Lewy body diseases, a family of progressive neurodegenerative disorders characterized by intra-neuronal cytoplasmic inclusions of α-synuclein. Its most defining features are bradykinesia, tremor, rigidity and postural instability. By the time PD manifests with motor signs, 70% of dopaminergic midbrain neurons are lost, and the disease is already in the middle or late stage. However, there are various non-motor symptoms occurring up to 20 years before the actual parkinsonism that are closely associated with profound deficiency of myocardial noradrenaline content and peripheral sympathetic denervation, as evidenced by neuroimaging experiments in recent years. Additionally, there is an inherent autotoxicity of catecholamines in the neuronal cells in which they are produced, forming toxic catecholaldehyde intermediates that make α-synuclein prone to aggregation, initiating a cascade of events that ultimately leads to neuronal death. The etiopathogenesis of PD and related synucleinopathies thus may well be a prototypical example of a catecholamine-regulated neurodegeneration, given that the synucleinopathy in PD spreads in synergy with central and peripheral catecholaminergic dysfunction from the earliest phases onward. That is why catecholamines and their metabolites, precursors, or derivatives in cerebrospinal fluid or plasma could be of particular interest as biomarkers for prodromal and de novo PD. Because there is great demand for such markers, this mini-review summarizes all catecholamine-related studies to date, in addition to providing profound neurochemical evidence on a systemic and cellular level to further emphasize this hypothesis and with emphasis on extracellular vesicles as a novel diagnostic and therapeutic incentive.

Serum Uric Acid, Serum Uric Acid to Serum Creatinine Ratio and Serum Bilirubin in Patients With Parkinson's Disease: A Case-Control Study.

BackgroundStudies have shown that a low serum uric acid (SUA) level associates with Parkinson’s disease (PD), but many of them did not exclude patients with impaired renal function. Studies on the association between serum bilirubin level and PD also are limited. This study determined the association between SUA level, SUA/serum creatinine (SCr) ratio and serum bilirubin levels in PD patients with normal renal and liver functions.MethodsThe PD patients from a neurological clinic, and the controls from the club for the elderly, were recruited into this study. The PD stage and motor and non-motor function were determined by the Hoehn-Yahr (H&Y) scale and unified Parkinson’s disease rating scale (UPDRS), respectively.ResultsSixty-one PD patients and 135 controls participated. The SUA/SCr ratio, but not SUA, was significantly lower in the PD patients than in the controls (4.12 ± 0.90 vs. 4.59 ± 1.04, P = 0.003). Serum total bilirubin (TB) and indirect bilirubin (IDB) were significantly higher in the PD patients (7.92 ± 3.67 µmol/L vs. 6.59 ± 2.78 µmol/L, P = 0.003 and 4.52 ± 2.48 µmol/L vs. 3.26 ± 1.82 µmol/L, P < 0.001), respectively. Serum TB and IDB, but not SUA or SUA/SCr ratio, were associated negatively with PD stages (P = 0.010 and P = 0.014, respectively). There was no association between TB, IDB, SUA or SUA/SCr ratio and PD disease duration or motor subtypes. No significant correlation was found between SUA or SUA/SCr ratio, serum TB and IDB.ConclusionThe SUA/SCr ratio is more sensitive than SUA in determining their association with PD. The high serum TB and IDB levels in PD patients compared with the controls suggest that serum bilirubin might play a role in the pathogenesis of PD. However, the lack of association between SUA or the SUA/SCr ratio and serum TB or IDB suggests that these two biomarkers play a different role in the etiopathogenesis of PD.

Brain-First versus Gut-First Parkinson's Disease: A Hypothesis.

Parkinson’s disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the vagus. Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence— reviewed herein. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature.

Rotenone: from modelling to implication in Parkinson's disease.

Rotenone ([2R-(2α,6aα,12aα)]-1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-[1]benzopyran[3,4-b]furo [2,3-h][1]benzopyran-6(6aH)-one) is a naturally occurring compound derived from the roots and stems of Derris, Tephrosia, Lonchocarpus and Mundulea plant species. Since its discovery at the end of the 19th century, rotenone has been widely used as a pesticide for controlling insects, ticks and lice, and as a piscicide for management of nuisance fish in lakes and reservoirs. In 2000, Betarbet et al. reproduced most of the behavioural, biochemical and pathological features of Parkinson's disease (PD) in rotenone-treated rats. Since that time, rotenone has received much attention as it would be one of the environmental neurotoxins implicated in etiopathogenesis of PD. Moreover, it represents a common experimental model to investigate the underlying mechanisms leading to PD and evaluate the new potential therapies for the disease. In the current general review, we aimed to address recent advances in the hazards of the environmental applications of rotenone and discuss the updates on the rotenone model of PD and whether it is implicated in the etiopathogenesis of the disease.

Neurochemical and Behavior Deficits in Rats with Iron and Rotenone Co-treatment: Role of Redox Imbalance and Neuroprotection by Biochanin A.

Increasing evidences show that the etiology of Parkinson's disease (PD) is multifactorial. Studying the combined effect of several factors is becoming a hot topic in PD research. On one hand, iron is one of the essential trace metals for human body; on the other hand, iron may be involved in the etiopathogenesis of PD. In our present study, the rats with increased neonatal iron (120 μg/g bodyweight) supplementation were treated with rotenone (0.5 mg/kg) when they were aged to 14 weeks. We observed that iron and rotenone co-treatment induced significant behavior deficits (time-dependent) and striatal dopamine depletion in the male and female rats, while they did not do so when they were used alone. No significant change in striatal 5-hydroxytryptamine content was observed in the male and female rats with iron and rotenone co-treatment. Also, iron and rotenone co-treatment significantly decreased substantia nigra TH expression in the male rats. Furthermore, co-treatment with iron and rotenone significantly induced malondialdehyde increase and glutathione decrease in the substantia nigra of male and female rats. There was no significant change in cerebellar malondialdehyde and glutathione content of the rats co-treated with iron and rotenone. Interestingly, biochanin A significantly attenuated striatal dopamine depletion and improved behavior deficits (dose-dependently) in the male and female rats with iron and rotenone co-treatment. Biochanin A treatment also significantly alleviated substantia nigra TH expression reduction in the male rats co-treated with iron and rotenone. Finally, biochanin A significantly decreased malondialdehyde content and increased glutathione content in the substantia nigra of male and female rats with iron and rotenone co-treatment. Our results indicate that iron and rotenone co-treatment may result in aggravated neurochemical and behavior deficits through inducing redox imbalance and increased neonatal iron supplementation may participate in the etiopathogenesis of PD. Moreover, biochanin A may exert dopaminergic neuroprotection by maintaining redox balance.

Genetic analysis of CHCHD2 in a southern Spanish population

Researching genetic factors involved in Parkinson's disease (PD) is crucial to increase our knowledge about the pathophysiology of the disorder. A missense mutation has recently been reported within CHCHD2, a gene newly associated with autosomal dominant PD. Subsequent studies in different ethnic populations have not reached any conclusive result about the role of CHCHD2 in PD. Therefore, the aim of this study was to investigate the implication of this gene for a PD population from southern Spain (including 536 PD patients and 518 unrelated control subjects). We studied all 4 exons of CHCHD2 and their exon-intron boundary regions. Four variants were observed in non-coding regions. No significant differences were observed in the allele frequencies of these variants between patients and controls. Thus, our study suggests that CHCHD2 is probably not involved in the etiopathogenesis of PD in our population.

Thr105Ile (rs11558538) polymorphism in the histamine N-methyltransferase (HNMT) gene and risk for Parkinson disease: A PRISMA-compliant systematic review and meta-analysis.

Background/aims:Several neuropathological, biochemical, and pharmacological data suggested a possible role of histamine in the etiopathogenesis of Parkinson disease (PD). The single nucleotide polymorphism (SNP) rs11558538 in the histamine N-methyltransferase (HNMT) gene has been associated with the risk of developing PD by several studies but not by some others. We carried out a systematic review that included all the studies published on PD risk related to the rs11558538 SNP, and we conducted a meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Methods:We used several databases to perform the systematic review, the software Meta-DiSc 1.1.1 to perform the meta-analysis of the eligible studies, and the Q-statistic to test heterogeneity between studies.Results:The meta-analysis included 4 eligible case–control association studies for the HNMT rs11558538 SNP and the risk for PD (2108 patients, 2158 controls). The frequency of the minor allele positivity showed a statistically significant association with a decreased risk for PD, both in the total series and in Caucasians. Although homozygosity for the minor allele did not reach statistical significance, the test for trend indicates the occurrence of a gene–dose effect. Global diagnostic odds ratios (95% confidence intervals) for rs11558538T were 0.61 (0.46–0.81) for the total group, and 0.63 (0.45–0.88) for Caucasian patients.Conclusion:The present meta-analysis confirms published evidence suggesting that the HNMT rs11558538 minor allele is related to a reduced risk of developing PD.

The contribution of alpha synuclein to neuronal survival and function - Implications for Parkinson's disease.

The aggregation of alpha synuclein (α‐syn) is a neuropathological feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated α‐syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the α‐syn gene result in familial PD. The high correlation between α‐syn burden and PD has led to the hypothesis that α‐syn aggregation produces toxicity through a gain‐of‐function mechanism. However, α‐syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of α‐syn results in toxicity because of a toxic loss of necessary α‐syn function, following sequestration of functional forms α‐syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking α‐syn to PD and the knowledge gained from current α‐syn‐based animal models of PD. We will then interpret these data from the viewpoint of the α‐syn loss‐of‐function hypothesis and provide a potential mechanistic model by which loss of α‐syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies. The correlation between α‐synuclein burden and Parkinson's disease pathology has led to the hypothesis that α‐synuclein aggregation produces toxicity through a gain‐of‐function mechanism. However, in this review, we discuss data supporting the alternative hypothesis that the aggregation of α‐synuclein results in toxicity because of loss of necessary α‐synuclein function at the presynaptic terminal, following sequestration of functional forms of α‐synuclein into aggregates.

Editorial: Parkinson's disease: cell vulnerability and disease progression.

The hallmark of Parkinson Disease (PD) is the degeneration of dopaminergic neurons in thesubstantia nigra pars compacta (SNc) and the consequent striatal dopamine (DA) deficiency,although it is well recognized that neurodegeneration in PD goes beyond the SNc. Major advanceshave occurred in recent years on the molecular and pathophysiological basis of PD, howeverthere remain many questions and unknowns regarding SNc cells vulnerability, and the exactsignificance of Lewy bodies and alpha-synuclein (α-syn) aggregation process regarding diseaseonset and progression. This Research Topic discuss the etiopathogenesis of PD, presenting aseries of papers that provide up-to-date, state-of-the-art information on molecular and cellularmechanisms involved in the neurodegeneration process, neuroimmune pathways, the role offunctionalandanatomicalorganizationofthebasalgangliaasafactorofneuronalvulnerability,thepossibilitythatPDisapriondiseaseandthecellularresponsetoα-synaggregation.Understandingthe mechanisms underlying vulnerability of dopaminergic midbrain neurons and how pathologybecomes widespread are primary objectives of basic and clinical research in PD.Are dopaminergic and other neurons dying by the same pathogenic mechanisms? Do they alldietothesameextentoratthesamerate?Whatarethemoleculardeterminantsofsusceptibilitytothe disease? To gain insights into these questions, researchers mainly rely in animal models. Blesaand Przedborski (2014) provide a summary of the current knowledge of invivomodels of PD.Whereas PD can be sporadic, genetic or possibly related with toxic/infectious agents, a differentialpattern of cell loss among midbrain dopaminergic neurons is observed regardless of diseaseetiology suggesting that differential dopaminergic neuron vulnerability does not depend on thefactor triggering PD “perse” but on intrinsic properties of these specific cell groups. Here, Brichtaand Greengard (2014) provides an update review on the molecular basis underlying differentialvulnerability of midbrain dopaminergic neurons in PD. For example, for many years many studieshavesuggestedcalbindin(CB)asamarkertodistinguishbetweenmidbraindopaminergicneuronswithdifferentsusceptibilitytodegenerationinPD.AlthoughCBdopaminergicneuronsseemtobeless prone to MPTP-induced degeneration, Dopeso-Reyes et al. (2014) clearly demonstrated thattheseneuronsarenotgivingrisetonigro-striatalprojectionsandindeedCB-ir/TH-irneuronsonlyoriginate nigro-extrastriatal projections. This data sustain the presence of a potential imbalancebetweenthenigro-striatalandnigroextrastriatalsystemsinadvanceddiseasesstates.Also,Afonso-Oramas et al. (2014) revealed that midbrain dopaminergic axons are in close apposition to striatalvessels and perivascular astrocytes in rats and monkeys. The relative weight of this “vascularcomponent” within the meso-striatal pathway suggests a role in the pathophysiology of PD.Aging is another major risk factor for developing PD. Rodriguez et al. (2014) reviewedsimilarities between neurodegeneration in PD and aging. The progressive course of aging andPD could be induced by the same multi-factorial etiology, including astrocytic and microgliaalterations, anomalous action of different proteins, mitochondrial disturbances, alterations of themitophagy or the ubiquitin-proteasome system and oxidative stress. Proteins involved in PD suchas α-syn, PINK1 or DJ-1, are also involved in aging. All these mechanisms of degeneration are

Differential protein profile of PC12 cells exposed to proteasomal inhibitor lactacystin

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and recent studies implicate a central role for ubiquitin–proteasome system (UPS) impairment in the etiopathogenesis of PD. To explore the possible role of UPS dysfunction in PD and the proteins involved, PC12 cells were treated with 10μM lactacystin, a 20S proteasome inhibitor, for 24h. Lactacystin induced cell death and α-synuclein-positive inclusions in cytoplasm. Following two-dimensional difference in-gel electrophoresis (2-D DIGE) which was used to separate the cellular proteins, the proteins that were significantly altered were analyzed and identified. Proteomic study identified 6 differentially expressed proteins between lactacystin-treated and control cells in this study. Four proteins (heat shock 70kDa protein 8, 78kDa glucose-regulated protein, serine proteinase inhibitor clade B member 6 and aldehyde reductase) were increased and 2 proteins (peripherin and tyrosine hydroxylase) were decreased following proteasomal inhibition. The results revealed that PC12 cells treated with 10μM lactacystin for 24h could be used as a cellular model of PD. The proteins identified in the present indicate not only the damage of proteasomal inhibition to the cells but also the possible responses of the cells. These data show that proteomic study may provide information relevant to biological basis for PD and potential new treatment targets.

EIF4G1 Ala502Val and Arg1205His variants in Chinese patients with Parkinson disease

Growing evidences show that genetic abnormalities play an important role in the etiopathogenesis of Parkinson disease (PD). At least 18 genetic loci and 13 disease-related genes for parkinsonism have been identified. Recently, the p.Ala502Val and p.Arg1205His variants in the eukaryotic translation initiation factor 4-gamma 1 gene (EIF4G1) were found to be associated with PD. To evaluate whether the EIF4G1 p.Ala502Val and p.Arg1205His variants are related to PD in Chinese Han population, we conducted genetic examination of these two variants in 425 PD patients from Mainland China and none was found in our patients. We did identify a known non-pathogenic polymorphism c.3660C>T (p.Ala1220Ala, rs143852330) in a 73-year-old male patient. Our results, consistent with other recent reports, suggest that the EIF4G1 p.Ala502Val and p.Arg1205His variants are a rare cause of PD, at least in Chinese population.

Brain transcriptomic profiling in idiopathic and LRRK2-associated Parkinson's disease

LRRK2 mutations are the most common genetic cause of Parkinson's disease (PD). We performed a whole-genome RNA profiling of locus coeruleus post-mortem tissue, a histopathologically affected brain tissue in PD, from idiopathic PD (IPD) and LRRK2-associated PD patients. The differentially expressed genes found in IPD and LRRK2-associated PD are involved in the gene ontology terms of synaptic transmission and neuron projection. In addition, differentially expressed genes in the IPD group are associated with immune system related pathways. Specifically, the study performed highlights the presence of differential expression of genes located in the chromosome 6p21.3 belonging to the class II HLA. Our findings support the hypothesis of a potential role of neuroinflammation and the involvement of the HLA genetic area in IPD pathogenesis. Future studies are necessary to shed light on the relation of immune system related pathways in the etiopathogenesis of PD.

Clinical features of Parkinson disease when onset of diabetes came first

Recent literature suggests that diabetes is a risk factor for Parkinson disease (PD). We investigated the clinical features of patients with idiopathic PD (IPD) in whom the onset of diabetes came first. We designed a case-control study. From the cohort of all new patients with IPD free of vascular disease (n = 783) admitted and evaluated at our institute over a 3-year period (2007-2010), we included all the patients with a diagnosis of diabetes prior to PD onset (n = 89) and a control group (n = 89) matched (1:1) for gender, body mass index (± 1 kg/m(2)), and duration of PD (± 1 year). The Unified Parkinson's Disease Rating Scale (UPDRS) motor score was the primary endpoint. At study entry, patients with diabetes were similar to controls in terms of most demographic, lifestyle, and general medical features with exception of statins (18% vs 3.4%; p = 0.003). However, diabetes was associated with higher UPDRS motor (22.3 ± 9.0 vs 19.3 ± 7.9; p = 0.019) and activities of daily living (9.7 ± 5.1 vs 8.3 ± 4.3; p = 0.049) scores, more severe Hoehn & Yahr staging (p = 0.009), and higher treatment doses of levodopa (mg/day, 448 ± 265 vs 300 ± 213; p < 0.0001; mg/kg/day, 5.8 ± 4.0 vs 3.8 ± 2.9; p < 0.0001). Onset of diabetes before the onset of PD appears to be a risk factor for more severe PD symptoms. These findings support the hypothesis that diabetes has a role in the etiopathogenesis of PD. Neurologists should be aware of the potential impact of diabetes on overall PD management.

Impaired CD200–CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: Roles of aging, superoxide, NADPH oxidase, and p38 MAPK

CD200–CD200R signaling holds microglia in a quiescent state. Parkinson disease (PD) neurodegeneration may be associated with impairment of CD200–CD200R-mediated microglia silencing in the substantia nigra (SN). In this study, an anti-CD200R blocking antibody (ACDR) selectively and significantly enhanced the susceptibility of dopaminergic neurons to neurotoxicity induced by rotenone (Rot) and iron (Ir) in mesencephalic neuron/glia cultures. Microglia were shown to mediate dopaminergic neurotoxicity induced by ACDR/Rot (combination of ACDR and Rot) and ACDR/Ir (combination of ACDR and Ir). ACDR significantly enhanced the microglial activation induced by Rot and Ir in neuron/glia cultures. NADPH oxidase-mediated superoxide generation was a key contributor to dopaminergic neurotoxicity induced by ACDR/Rot and ACDR/Ir. p38 MAPK contributed to NADPH oxidase activation induced by ACDR/Rot and ACDR/Ir. Interestingly, there were a decrease in CD200 expression (mRNA and protein) and an enhancement of microglial response (MHCII mRNA and ICAM-1 protein) in the rat SN with aging. ICAM-1 expression was significantly inversely correlated with CD200 expression. These results strongly indicate the participation of SN CD200–CD200R dysfunction in the etiopathogenesis of PD and provide a new insight into the molecular mechanisms underlying the involvement of aging in PD and help to elucidate the mechanisms of the combined involvement of immune/inflammatory factors, environmental substances, and aging in PD.