Cells Of Parkinson's Disease Patients Research Articles

Imbalance of Circulating Tfh/Tfr Cells in Patients With Parkinson's Disease.

Background: Follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are essential for B cell differentiation, germinal center formation, and humoral immune responses. Immunity and inflammation have been thought to be involved in Parkinson's disease (PD). In this study, we aimed to identify whether circulating Tfh and Tfr (cTfh and cTfr) cells contribute to PD.Methods: Thirty-nine PD patients and 26 health controls (HCs) were enrolled. The numbers of cTfh (CD4+CXCR5+PD-1+) cells and cTfr (CD4+CXCR5+CD25hiCD127low) cells were analyzed via flow cytometry. The serum concentrations of interleukin (IL)-4, IL-10, IL-21, and transforming growth factor (TGF)-β were examined by cytometric bead array.Results: The percentage of cTfh cells among CD4+ T cells in PD patients was significantly higher than that in HCs [3.68% (2.64–5.70%) vs. 1.94% (1.32%−2.99%), P < 0.001], while the percentage of cTfr cells among CD4+ T cells in PD patients was slight decreased but without significance [1.05% (0.62–1.54%) vs. 1.3% (0.63–1.90%), P > 0.05]. The percentage of CD19+ B cells in peripheral blood mononuclear cells was significantly lower in PD patients than in HCs [5.35% (4.13–9.38%) vs. 8.68% (5.61–12.93%), P = 0.014]. The serum concentrations of IL-4, IL-10, IL-21, and TGF-β in PD patients did not differ significantly from those in HCs (P > 0.05). There was a positive trend of the correlation between the number of cTfh and the serum IL-4 concentrations in PD patients (P = 0.032, r = 0.353). There was a positive trend of the correlation between the number of cTfr and the serum IL-10 concentrations in PD patients (P = 0.047, r = 0.328), A positive trend of the correlation were found for the serum concentration of IL-21 with H-Y stage (r = 0.356, P = 0.026) and UPDRS-III score (r = 0.347, P = 0.030).Conclusions: These results indicate that an imbalance of cTfh and cTfr cells may be involved in the chronic progression of PD, and IL-21 may be a biomarker for monitoring the severity of this disease.

Exosomes from Human Periapical Cyst-MSCs: Theranostic Application in Parkinson's Disease.

The scientific community continuously strives to get new disease models, to discover early markers or novel therapeutic approaches, improving the diagnosis and prognosis of several human pathologies. Parkinson's Disease (PD) is characterized by a long asymptomatic phase, characterized by a selective loss of dopaminergic neurons. Recently, the human Periapical Cyst-Mesenchymal Stem Cells (hPCy-MSCs) have been differentiated in functional dopaminergic neurons: such oral-derived MSCs and the hPCy-MSCs-derived exosomes may represent a strategic and useful in vitro study-model, as well as intriguing therapeutic carriers. Circadian rhythm (CR) alteration variously impacts on PD pathways: an interesting research target is represented by the analysis of the exosomes released by dopaminergic neurons, derived from neural-differentiated hPCy-MSCs, after having reproduced in-vitro PD-like conditions. This review aims to describe the crosstalk among some aspects of circadian rhythm related to the onset of PD and the exosomes released by cells of PD patients. More in detail: the first part of this article will describe the main characteristics of circadian rhythm and the involvement of the exosomes found to be effective in the pathogenesis of PD. Finally, the authors will suggest how those exosomes derived from dopaminergic neurons, obtained by oral-derived stem cells (hPCy-MSCs) may represent a smart model for the in vitro research on PD, to find new biomarkers, to test new drugs or, fatally, to find new pathways applicable in future therapeutic approaches.

Stem cells therapy for Parkinson's disease: An update review

Stem cells therapy is the one of exciting potential for Parkinson's disease (PD) treatment because of the superiority for reducing progression of dopamine (DA) neurons degeneration in substantia nigra of middle brain, which causes the motor symptoms and nonmotor symptoms of PD. The development of stem cells therapy for PD is quite slow because it has problems related to patient selection, safety, and ethical problems. So far, there have been no stem cell research for PD publications until phase IV according to FDA clinical trials. Current researches have only reached phase I-III, which some studies are still in the research process and not yet published. At present, stem cell researchers are still looking for the best method for transplanting stem cells in PD patients. Optimization of stem cell therapy for PD can be done by: (1) choosing the right donor stem cells, (2) inducing and selecting DA neurons appropriately, (3) conducting valid preclinical research, (4) optimizing the host brain environment. Further studies are needed to answer some crucial questions about the different issues in stem cell therapy. Accordingly, stem cell based therapy for PD also needed more complementary evaluation in both basic and clinical study areas.

Autoimmunity in Parkinson's Disease: The Role of α-Synuclein-Specific T Cells.

Evidence from a variety of studies implicates a role for the adaptive immune system in Parkinson's disease (PD). Similar to multiple sclerosis (MS) patients who display a high number of T cells in the brain attacking oligodendrocytes, PD patients show higher numbers of T cells in the ventral midbrain than healthy, age-matched controls. Mouse models of the disease also show the presence of T cells in the brain. The role of these infiltrating T cells in the propagation of disease is controversial; however, recent studies indicate that they may be autoreactive in nature, recognizing disease-altered self-proteins as foreign antigens. T cells of PD patients can generate an autoimmune response to α-synuclein, a protein that is aggregated in PD. α-Synuclein and other proteins are post-translationally modified in an environment in which protein processing is altered, possibly leading to the generation of neo-epitopes, or self-peptides that have not been identified by the host immune system as non-foreign. Infiltrating T cells may also be responding to such modified proteins. Genome-wide association studies (GWAS) have shown associations of PD with haplotypes of major histocompatibility complex (MHC) class II genes, and a polymorphism in a non-coding region that may increase MHC class II in PD patients. We speculate that the inflammation observed in PD may play both pathogenic and protective roles. Future studies on the adaptive immune system in neurodegenerative disorders may elucidate steps in disease pathogenesis and assist with the development of both biomarkers and treatments.

SNCA variants and alpha-synuclein level in CD45+ blood cells in Parkinson’s disease

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder. Impaired metabolism of alpha-synuclein (SNCA) and its aggregation are implicated in PD pathogenesis. SNCA has been identified as a highly significant genetic risk loci associated with the sporadic form of PD in across populations in GWAS and replicative studies.In this study we conducted a genetic analysis of five SNCA single nucleotide polymorphisms (SNPs) (rs356219, rs2619364, rs11931074, rs2583988, rs356168) in 458 PD patients and 353 from North-West region of Russia. We also assessed an association of studied SNPs with alpha-synuclein levels in homogeneous cell fraction of CD45+ blood cells in PD patients and controls. An association with PD was shown for SNPs rs356219, rs11931074, rs356168. After correction for covariates the significant association with the disease only for rs11931074 and rs356168 was shown. Alpha-synuclein level in peripheral blood CD45+ cells was significantly increased in PD patients compared to control subjects (р = 0.02). The effect of SNCA rs356219 and rs356168 on CD45+ alpha-synuclein level in PD patients and control groups was shown. At the same tame the increase of CD45+ alpha-synuclein level in PD patients was revealed only in risk allele carriers as for rs356219 and rs356168 SNPs. Therefore, our study was the first that demonstrated the increased level of alpha-synuclein in CD45+ blood cells in PD patients and showed that it could be influenced by SNCA rs356168 and rs356219. In conclusion we confirmed the significance of the SNCA locus in the PD development.

Parkinson's disease (PD) is the most common neurodegenerative disease

Metabolic impairment of alpha-synuclein protein is considered to be the central event in PDpathogenesis. Recent studies explored usage of alpha-synuclein in peripheral fluids as a biomarker of PD, however alpha-synuclein level in the CSF and plasma is considered to be affected by hemolysis. In order to avoid contamination of a lymphocyte fraction by erythrocytes, we have proposed an algorithm based on measurements of alpha-synuclein levels in the homogeneous CD45+ cell blood fraction. For this study we formed a group of PD patients (N=14) and a control group without the neurological disorders (N=17). We found an increase in the level of the total alpha-synuclein in CD45+ cells of PD patients compared to controls (p = 0,04), and revealed a direct correlation between the level of dopamine in plasma and level of total alpha-synuclein in CD45+ cells in the control group (r=0,71, p = 0,007).The level of alpha-synuclein in CD45+ cells could be suggested as possible PD biomarker.

Inflammatory dysregulation of blood monocytes in Parkinson's disease patients

Despite extensive effort on studying inflammatory processes in the CNS of Parkinson's disease (PD) patients, implications of the peripheral immune system are still poorly understood. In particular, the role of peripheral blood monocytes remains elusive. Here, we set out to obtain a comprehensive picture of circulating myeloid cells in PD patients. We applied a human primary monocyte culture system and flow cytometry based techniques to functionally characterize monocytes from PD patients during disease.

Dyskinesia in Parkinson's Disease Therapy

L-DOPA is still regarded as the standard pharmacotherapy for the treatment of the motor symptoms of Parkinson's disease (PD). However, the efficacy of this drug is limited by the emergence of dystonic and choreic involuntary movements, generally referred to as dyskinesia. Current interventions to treat dyskinesia are mainly based on continuous delivery of L-DOPA, administration of glutamatergic drugs (i.e., amantadine), replacement or combined administration of L-DOPA with less dyskinetic, albeit less effective, dopaminergic agonists, and deep-brain stimulation of discrete regions of the basal ganglia. Preclinical research, on the other hand, is searching for novel approaches to the treatment of L-DOPA-induced dyskinesia, targeting alternative neurotransmitter systems, such as the serotonin, adenosine, and opioid systems, or identifying abnormalities in intracellular signal transduction and synaptic plasticity associated to this condition. This Special Issue discusses recent breakthroughs in this direction and, at the same time, provides an update of the clinical features and management of L-DOPA-induced dyskinesia. The article by J. Guridi et al. describes the mechanisms underlying the various forms of dyskinesia produced by prolonged administration of L-DOPA. Basic pathophysiological mechanisms and current treatments are presented in detail and critically discussed. I. Aviles-Olmos et al. focus on the comparison between L-DOPA-induced dyskinesia and graft-induced dyskinesia, an analogous condition observed in response to transplantation of fetal dopaminergic cells in PD patients. This article also provides a timely discussion of the use of gene therapy in PD and of its effects on dyskinesia. The article by N. Tambasco et al. presents the clinical and epidemiological characteristics of dyskinesia and describes the management of this condition, based on the use of various types of dopaminergic agonists. On the same line, J. C. P. Piedad and A. E. Cavanna discuss more in detail the use of pramipexole, an agonist at dopamine D2-type receptors, in the treatment of dyskinesia. A number of signaling components potentially implicated in dyskinesia have been discovered during the last decade. In this regard, V. Ghiglieri et al. provide a comprehensive overview of the mechanisms and the possible pathological consequences of abnormalities affecting various forms of corticostriatal plasticity associated to L-DOPA-induced dyskinesia. Recently, studies have pointed to the serotonergic system as a key player in the aberrant effects produced by L-DOPA and linked to the emergence of dyskinesia. The article by S. Navailles and P. De Deurwaerdere describes the evidence at the basis of this hypothesis and discusses the use of therapeutic approaches designed to prevent this phenomenon. On the same subject, E. Shin et al. discuss the experimental and clinical evidence implicating the serotonin system in L-DOPA- and graft-induced dyskinesia. Drugs acting as antagonists at adenosine A2A receptors have attracted considerable interest as antiparkinsonian and antidyskinetic agents. The article by M. Morelli et al. provides a critical appraisal of the potential therapeutic properties of these compounds, as determined in experimental models of PD and L-DOPA-induced dyskinesia. Finally, G. Frazzitta et al. present an interesting study showing the beneficial effects produced on dyskinesia by intensive physiotherapeutic rehabilitation. These results are discussed with regard to similar studies performed in animal models of PD.

Induction of dopaminergic neuronal-like cells from CD44+ human amniotic fluids that are ameliorative to behavioral recovery in a Parkinson's disease rat model

Parkinson's disease (PD) is a common age-associated neurodegenerative disorder. To date, stem cell transplantation therapy has been developed to replace lost or damaged neural cells in PD patients, in whom dopaminergic neuron cells are lost. Here, we show that CD44+ human amniotic fluid cells (HuAFCs) can be induced to become functional dopaminergic neuronal-like cells invitro. Furthermore, when CD44+ or CD44- HuAFCs were transplanted into 6-hydroxydopamine (6-OHDA)-treated PD rats, the results indicated that CD44+ HuAFCs expressed multiple dopaminergic neuron cell markers and were ameliorative to behavioral recovery in PD rats after induction both invitro and invivo. CD44- HuAFCs did not fully differentiate into dopaminergic neuronal-like cells. When compared with CD44- HuAFCs, CD44+ HuAFCs showed increased activity in regeneration of dopaminergic neuron cell-like cells, increased migration distances, and improvement of animal behavior in the PD rat model. Therefore, CD44+ HuAFCs could be a source of dopaminergic neuronal-like cells with a potential use in cell-replacement therapy for PD.

Oxidative-stress-induced apoptosis in PBLs of two patients with Parkinson disease secondary to alpha-synuclein mutation

Alpha-synuclein has been implicated in the pathology of certain neurodegenerative diseases, including Parkinson disease (PD). Although the precise physiological and pathological role of alpha-synuclein is unclear, overexpression of the protein or its mutants may reduce cell viability. In this study we evaluated the apoptotic response to oxidative stress induced by 2-deoxy-d-ribose (dRib) in peripheral blood lymphocytes (PBLs) of two siblings with Parkinson disease secondary to A53T alpha-synuclein mutation. PBLs exposed to oxidative stress showed a higher percentage of apoptotic cells in PD patients than in controls. However in cells of PD patients, the increase of apoptotic response was lower than in controls, suggesting that cells of PD patients have greater "resistance" to oxidative stress. We conclude that other environmental agents could play a key role in inducing programmed cell death in cells of PD patients with mutant alpha-synuclein.

Hypocretin (orexin) cell loss in Parkinson's disease

It has recently been reported that Parkinson’s disease (PD) is preceded and accompanied by daytime sleep attacks, nocturnal insomnia, REM sleep behaviour disorder, hallucinations and depression, symptoms which are frequently as troublesome as the motor symptoms of PD. All these symptoms are present in narcolepsy, which is linked to a selective loss of hypocretin (Hcrt) neurons. In this study, the Hcrt system was examined to determine if Hcrt cells are damaged in PD. The hypothalamus of 11 PD (mean age 79±4) and 5 normal (mean age 77±3) brains was examined. Sections were immunostained for Hcrt-1, melanin concentrating hormone (MCH) and alpha synuclein and glial fibrillary acidic protein (GFAP). The substantia nigra of 10 PD brains and 7 normal brains were used for a study of neuromelanin pigmented cell loss. The severity of PD was assessed using the Hoehn and Yahr scale and the level of neuropathology was assessed using the Braak staging criteria. Cell number, distribution and size were determined with stereologic techniques on a one in eight series.We found an increasing loss of hypocretin cells with disease progression. Similarly, there was an increased loss of MCH cells with disease severity. Hcrt and MCH cells were lost throughout the anterior to posterior extent of their hypothalamic distributions. The percentage loss of Hcrt cells was minimal in stage I (23%) and was maximal in stage V (62%). Similarly, the percentage loss of MCH cells was lowest in stage I (12%) and was highest in stage V (74%). There was a significant increase (P=0.0006, t=4.25, df=15) in the size of neuromelanin containing cells in PD patients, but no difference in the size of surviving Hcrt (P=0.18, t=1.39, df=14) and MCH (P=0.28, t=1.39, df=14) cells relative to controls.In summary, we found that PD is characterized by a massive loss of Hcrt neurons. Thus, the loss of Hcrt cells may be a cause of the narcolepsy-like symptoms of PD and may be ameliorated by treatments aimed at reversing the Hcrt deficit. We also saw a substantial loss of hypothalamic MCH neurons. The losses of Hcrt and MCH neurons are significantly correlated with the clinical stage of PD, not disease duration, whereas the loss of neuromelanin cells is significantly correlated only with disease duration. The significant correlations that we found between the loss of Hcrt and MCH neurons and the clinical stage of PD, in contrast to the lack of a relationship of similar strength between loss of neuromelanin containing cells and the clinical symptoms of PD, suggests a previously unappreciated relationship between hypothalamic dysfunction and the time course of the overall clinical picture of PD.

Microarray expression analysis of gad mice implicates involvement of Parkinson's disease associated UCH-L1 in multiple metabolic pathways

Parkinson's disease (PD) is thought to be caused by environmental and genetic factors. Mutations in four genes, α-synuclein, parkin, DJ-1, and UCH-L1, have been identified in autosomal inherited forms of PD. The pathogenetic cause for the loss of neuronal cells in PD patients, however, remains to be determined. Due to the rarity of mutations in humans with PD, the analysis of animal models might help to further gain insights into the pathogenesis of familial PD. For UCH-L1, deficiency has been described in gad mice leading to axonal degeneration and formation of spheroid bodies in nerve terminals. Here, we investigated the gene expression pattern of the brain of 3-month-old Uch-l1-deficient gracile axonal dystrophy ( gad) mice by microarray analysis. A total of 146 genes were differentially regulated by at least a 1.4-fold change with 103 being up-regulated and 43 being down-regulated compared with age and sex matched wildtype littermate mice. The gene products with altered expression are involved in protein degradation, cell cycle, vesicle transport, cellular structure, signal transduction, and transcription regulation. Most of the genes were modestly regulated, which is in agreement that severe alteration of these pathways might be lethal. Among the genes most significantly down-regulated is the brain-derived neurotrophic factor which might be one aspect of the pathogenesis in gad mice. Interestingly, several subunits of the transcription factor CCAAT/enhancer binding protein are up-regulated, which plays a central role in most altered pathways.

Microarray expression analysis of gad mice implicates involvement of Parkinson's disease associated UCH-L1 in multiple metabolic pathways

Parkinson's disease (PD) is thought to be caused by environmental and genetic factors. Mutations in four genes, α-synuclein , parkin , DJ-1 , and UCH-L1 , have been identified in autosomal inherited forms of PD. The pathogenetic cause for the loss of neuronal cells in PD patients, however, remains to be determined. Due to the rarity of mutations in humans with PD, the analysis of animal models might help to further gain insights into the pathogenesis of familial PD. For UCH-L1, deficiency has been described in gad mice leading to axonal degeneration and formation of spheroid bodies in nerve terminals. Here, we investigated the gene expression pattern of the brain of 3-month-old Uch-l1-deficient gracile axonal dystrophy ( gad ) mice by microarray analysis. A total of 146 genes were differentially regulated by at least a 1.4-fold change with 103 being up-regulated and 43 being down-regulated compared with age and sex matched wildtype littermate mice. The gene products with altered expression are involved in protein degradation, cell cycle, vesicle transport, cellular structure, signal transduction, and transcription regulation. Most of the genes were modestly regulated, which is in agreement that severe alteration of these pathways might be lethal. Among the genes most significantly down-regulated is the brain-derived neurotrophic factor which might be one aspect of the pathogenesis in gad mice. Interestingly, several subunits of the transcription factor CCAAT/enhancer binding protein are up-regulated, which plays a central role in most altered pathways.