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The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn. However, the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons, which promotes the spread of α-syn pathology. In this article, we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis, highlighting the relationships between glial responses and the spread of α-syn pathology.
Subject(s)
Humans , Parkinson Disease/pathology , alpha-Synuclein/metabolism , Dopaminergic Neurons/metabolism , Pars Compacta/metabolismABSTRACT
The way sporadic Parkinson's disease (PD) is perceived has undergone drastic changes in recent decades. For a long time, PD was considered a brain disease characterized by motor disturbances; however, the identification of several risk factors and the hypothesis that PD has a gastrointestinal onset have shed additional light. Today, after recognition of prodromal non-motor symptoms and the pathological processes driving their evolution, there is a greater understanding of the involvement of other organ systems. For this reason, PD is increasingly seen as a multiorgan and multisystemic pathology that arises from the interaction of susceptible genetic factors with a challenging environment during aging-related decline.
Subject(s)
Humans , Parkinson Disease/pathology , Gastrointestinal Tract , Risk Factors , Gastrointestinal Microbiome , Prodromal Symptoms , alpha-SynucleinABSTRACT
Parkinson's disease (PD) is the most common neurodegenerative movement disease. It is featured by abnormal alpha-synuclein (α-syn) aggregation in dopaminergic neurons in the substantia nigra. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates, to maintain cellular homeostasis. Corynoxine B (Cory B), a natural alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks., has been reported to promote the clearance of α-syn in cell models by inducing autophagy. However, the molecular mechanism by which Cory B induces autophagy is not known, and the α-syn-lowering activity of Cory B has not been verified in animal models. Here, we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2. Depletion of HMGB1/2 impaired Cory B-induced autophagy. We showed for the first time that, similar to HMGB1, HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinase III activity both under basal and stimulated conditions. By applying cellular thermal shift assay, surface plasmon resonance, and molecular docking, we confirmed that Cory B directly binds to HMGB1/2 near the C106 site. Furthermore, in vivo studies with a wild-type α-syn transgenic drosophila model of PD and an A53T α-syn transgenic mouse model of PD, Cory B enhanced autophagy, promoted α-syn clearance and improved behavioral abnormalities. Taken together, the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinase III activity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.
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GBA1 is one of the common risk genes of Parkinson′s disease (PD), which encodes glucocerebrosidase. It is difficult to distinguish PD patients with heterozygous variants of GBA1 ( GBA1-PD) from idiopathic Parkinson′s disease patients, but GBA1-PD tends to progress faster, be more severe, and be more likely to be associated with cognitive impairment and other non-motor symptoms. The pathological mechanism of the increased risk of PD in GBA1 heterozygous variant carriers may be related to autophagy-lysosome dysfunction and mitochondrial dysfunction. Targeted therapy for GBA1 is expected to become a new direction of precision therapy for PD. In this article, the epidemiology and clinical features of GBA1-PD, the possible pathogenesis of GBA1 variation, and the therapeutic strategies for GBA1-PD were elaborated.
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Dementia with Lewy bodies(DLB)is the second most common neurodegenerative dementia after Alzheimer's Disease(AD). This article will mainly elaborate the relationship between DLB and blood-brain barrier(BBB)from the following five aspects: (1)The structure and function of BBB; (2)In vivo assessment methods for the blood-brain barrier damage; (3)Evidence for the damage of blood-brain barrier in DLB; (4)The relationship between α-synuclein and the blood-brain barrier; (5)The relationship between APOE and the blood-brain barrier.Future research should focus on the pathogenesis of BBB damage in DLB patients, by which new drug targets for disease diagnosis and treatment may be found.
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Multiple system atrophy(MSA)is a rare and fatal neurodegenerative disease occurring in middle-aged and older people, mainly characterized by autonomic nervous system and motor dysfunction.At present, there is no effective method to prevent or reverse its progression, and its treatment is mostly symptom-based, with limited success.A large number of interventional trials have been conducted to explore new treatments for MSA, but there is no clearly effective disease-modifying therapy, probably as a result of poor understanding of the pathophysiological and physiological mechanisms underlying MSA, which may be influenced by multiple factors.The purpose of this paper is to review the existing intervention trials for disease modification therapy of MSA and to discuss the outlook for new therapeutic targets.
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The remodeling of phospholipid includes two processes: deacylation and reacylation. It realizes the conversion of nascent phospholipids to mature phospholipids by changing the length and types of fatty acids at specific sites of phospholipids, which is a key step in phospholipid metabolism. Phospholipids are not only the basic components of biological membranes, but also participate in the transduction of many molecular signals in cells. Therefore, phospholipid remodeling disorders can affect the structure and function of cell membranes, as well as the activity of membrane proteins, causing a series of intricate signaling cascades, and finally lead to many pathological changes including neurodegeneration. This paper reviews the basic process of phospholipid remodeling and the involvement of its key enzymes, calcium independent group VIA phospholipase A2 (iPLA2β), peroxiredoxin 6 (PRDX6), calcium independent group VIB phospholipase A2 (iPLA2γ) as well as acyl-CoA lysocardiolipin acyltransferase 1 (ALCAT1) in the pathology of Parkinson's disease. The mutations in the gene encoding iPLA2β, PLA2G6, have been widely reported to be directly related to hereditary Parkinson disease-14 (PARK14). Here we focus on the molecular mechanism of iPLA2β in the development of Parkinson's disease, mainly involving phospholipid fatty acid metabolism disorders, mitochondrial physiology abnormalities and α-synuclein aggregate formation and other aspects, which will help to understand the role of phospholipid remodeling in Parkinson's disease, and provide new clues for the development of new Parkinson's disease diagnosis and treatment strategies.
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Objective:To investigate the effect of interfering S-phase kinase associated protein 1 (SKP1) gene on apoptosis in Parkinson's disease(PD) cell model induced by 1-methyl-4-phenyl-pyridine ion (MPP+ ) and the mechanism of ubiquitin proteasome system degradation of α-synuclein (α-syn) influence.Methods:SH-SY5Y cells were divided into control group, MPP+ group, SKP1 interference group, and SKP1 interference+ MG132(UPS inhibitor) group.The cells in the control group were cultured normally. The cells in the latter three groups were incubated with MPP+ (0.5 mmol/L) for 24 h as PD model cells.The cells in SKP1 interference group were transfected with lentivirus SKP1-siRNA, and the cells in SKP1 interference+ MG132 group were transfected with lentivirus SKP1 siRNA and added with MG132 (0.5 μmol/L) for 24 h. The protein levels and mRNA levels of SKP1, microtubule-associated protein light chain 3 (LC3), lysosome-associated membrane protein (LAMP), α-syn, ubiquitin activating enzyme E1 (UBE1), parkin, and p27 in cells were detected by Western blot and RT-PCR.Flow cytometry was used to detect cell apoptosis and cycle level, and CCK-8 method was used to detect cell proliferation level.Co-immunoprecipitation method was used to explore the interaction between SKP1 and p27. SPSS 23.0 software was used for statistical analysis. One-way ANOVA was used for comparison among groups, and LSD test was used for further pairwise comparison.Results:RT-PCR and Western blot results showed that the mRNA levels and protein levels of autophagy related proteins and ubiquitin related proteins LC3, LAMP2, α-syn, UBE1, parkin and p27 in the four groups were statistically significant(mRNA: F=99.155, 43.028, 138.464, 28.200, 22.009, 28.147, all P<0.05; F=245.517, 157.634, 315.920, 2 336.472, 477.429, 2 350.201, all P<0.05). The mRNA and protein levels of LC3, Lamp2, α-syn and p27 in SKP1 interference group were lower than those in MPP+ group (all P<0.05), while the mRNA and protein levels of UBE1 and parkin were higher than those in MPP+ group (all P<0.05). The mRNA and protein levels of LC3, α-syn and p27 in SKP1 interference+ MG132 group were higher than those in SKP1 interference group (all P<0.05), and the mRNA and protein levels of UBE1 and parkin were lower than those in SKP1 interference group (all P<0.05). The results of flow cytometry and CCK-8 method showed that the apoptosis rate and cell inhibition rate among the four groups were significantly different( F=2 749.420, 171.508, both P<0.05). The apoptosis rate of SKP1 interference group was lower than that of MPP+ group ((8.22±0.25)%, (15.30±0.21)%, P<0.05), while the cell inhibition rate of SKP1 interference group was lower than that of MPP+ group((26.31±3.73)%, (55.05±3.84)%, P<0.05). The apoptosis rate of SKP1 interference+ MG132 group ((9.49±0.07)%) was higher than that of SKP1 interference group, and the cell inhibition rate ((36.06±2.85)%) was higher than that of SKP1 interference group (both P<0.05). The results of immunoprecipitation method showed that P27 decreased after SKP1 immunoprecipitation. Conclusion:After SKP1 gene was interfered, the autophagy function of PD cells decreased, which may be related to parkin promoting α-syn ubiquitination, activating UBE1/ Parkin-mediated UPS pathway to degrade α-syn, and mediating P27 to inhibit apoptosis.
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Objective:To investigate the relationship between plasma phosphorylated α-synuclein (ps129-α-syn) and cognitive function in Parkinson disease (PD).Methods:This study recruited 90 PD patients who were hospitalized in the Department of Neurology, Henan province people's hospital from March 2019 to June 2020.Forty healthy middle-aged and elderly people with normal cognitive function who came to the hospital for physical examination were selected during the same period.Clinical characteristics and blood samples were collected.Patients with PD were classified into those with normally cognitive (PD-NC), mild cognitive impairment (PD-MCI), and dementia (PDD). The enzyme-linked immunosorbent assay was used to measure the plasma ps129-α-syn.Correlations between plasma ps129-α-syn and clinical characteristics such as disease duration, Hoehn-Yahr stage (H-Y), unified Parkinson's disease rating scale (UPDRS), Montreal cognitive assessment (MoCA), 14-item Hamilton anxiety rating scale (HAMA-14), the 24-item Hamilton depression rating scale (HAMD-24), levodopa equivalent daily dosage (LEDD), the scale of outcomes in Parkinson's disease for autonomic symptoms, SCOPA-AUT) were analyzed using Pearson or Spearman correlation analysis.Multiple linear regression analysis was used to evaluate the factors affecting the cognitive function of PD.Results:Plasma ps129-α-syn in PD patients was higher than that in healthy controls((19.44±8.93)μg/L, (10.78±5.87)μg/L, ( t=5.615, P<0.01). Plasma ps129-α-syn was higher in PD-MCI group((19.64±7.77)μg/L)and PDD group((23.79±9.47)μg/L) compared with that in PD-NC group((13.37±5.40)μg/L)( P<0.05). Plasma ps129-α-syn was positively correlated with H-Y ( r=0.404, P<0.01), UPDRS-Ⅲ( r=0.275, P=0.009), UPDRS-total ( r=0.211, P=0.046) and SCOPA-AUT( r=0.335, P=0.001). Plasma ps129-α-syn was negatively associated with MoCA ( r=-0.459, P<0.01). Multiple linear regression analysis suggested disease duration ( t=-4.618, P<0.01), ps129-α-syn( t=-3.792, P<0.01) and UPDRS-total ( t=-2.826, P=0.006) were independently associated with cognitive function.Plasma ps129-α-syn could discriminate between PD-NC and PD cognitive function impairment with an AUC of 0.7797 (95% CI: 0.686 3-0.873 2, P<0.01). Conclusions:Plasma ps129-α-syn is correlated with cognitive function and the severity of motor symptoms in PD patients, and have high sensitivity and specificity in diagnosing PD cognitive dysfunction.Therefore, plasma ps129-α-syn can serve as a biomarker to assess cognitive function in PD.
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Acupuncture can improve the motor and non-motor symptoms of Parkinson's disease, and the effect of acupuncture combined with drug therapy is better than that of drug therapy alone. The possible mechanism includes inhibiting α-synuclein aggregation, oxidative stress, and neuroinflammation, inhibiting the apoptosis of dopaminergic neurons, and achieving a neuroprotective effect. The points mainly selected for Acupuncture treatment for this disease are Zusanli (ST 36), Yanglingquan (GB 34), Taichong (LR 3), Xuehai (SP 10), and other points. Early use of acupuncture and acupuncture combined with medical treatment strategy is worthy of clinical application.
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Parkinson′s disease (PD) is a common neurodegenerative disease. Impaired balance between deposition and clearance of α-synuclein lies at the core of PD pathogenesis. The glymphatic system is a highly organized fluid transport system that is capable of removing brain waste. Emerging evidence revealed that glymphatic dysfunction plays a critical role in the pathogenesis of neurodegenerative diseases, yet study on its implication in PD is at its early stage. An in-depth study of the relationship between the function of the glymphatic system and α-synuclein clearance in PD may shed light on the pathogenesis and therapeutics of the disease.
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Objective: There are four currently motor features characterizing Parkinson's disease (PD). These includerigidity of muscles, bradykinesia, tremors at rest, and instability of posture. Along the course of PD, theimpairment of motor functions is commonly preceded by nonmotor symptoms (NMS) such as olfactory deficit,difficult swallowing (dysphagia), drooling (sialorrhea), constipation, urinary bladder dysfunction, depression,and sleep disorder. It was suggested that the enteric nervous system could be the initial site for the pathologicalprocess leading to PD. Materials and Methods: Six male adult control AS rats (normal control) and six maleadults AS/AGU rats (model of PD) were sacrificed. A rectangular strip from the body of the stomach and across-section from the duodenum were dissected and processed for histological staining with hematoxylin andeosin, and immunohistochemical staining for detection of nNOS (neuronal NOS), S100 protein (astrocytemarker), and alpha-synuclein (α-synuclein). Results: The histological analysis of the stomach and duodenum ofAS/AGU rats demonstrated necrotic smooth muscle cells of muscularis externa. The immunohistochemicalanalysis of AS/AGU rats showed a statistically significant increase in the expression of nNOS, S100 protein, andα-synuclein expression of myenteric plexuses compared to the control strain AS rats. Conclusion:Gastroduodenal tract of AS/AGU rats showed marked histopathological changes and immunohistochemicaloverexpression of nNOS, S100, and α-synuclein.
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This article is to investigate the effect of piperine on the small intestine of mice with Parkinson's disease with dementia(PDD). Ninety-six C57 BL/6 mice of SPF grade were randomly divided into 8 groups(male, 12 in each group): normal group, model group, autophagy inhibitor group(6-amino-3-methylpurine, 3 MA, 30 mg·kg~(-1)), autophagy activator group(rapamycin, 1 mg·kg~(-1)), low, medium, and high dose piperine groups(10, 20, 40 mg·kg~(-1)), and medopar group(112.5 mg·kg~(-1)). Except for the normal group, mice in each group were injected subcutaneously with reserpine(0.1 mg·kg~(-1)) once every 48 hours for 40 days. In addition, on the 20 th day of administration, except for the normal group, the mice in the other groups were subjected to bilateral common carotid artery occlusion to finally prepare PDD models. At the same time, each group was given the corresponding drug treatment once a day for 40 days. After the last administration, the behavioral changes of mice were observed by autonomic activity experiment and hot plate experiment. The expression levels of α-synuclein(α-syn) and tyrosine hydroxylase(TH) in the small intestine were detected by immunohistochemistry. The expression levels of beclin-1, microtubule-associated protein 1 light chain 3 B(LC3 B) and p62 in the small intestine were detected by immunofluorescence assay. Hematoxylin-eosin staining was used to observe the pathological morphology of small intestine tissues in each group. Enzyme-linked immunosorbent assay was adopted for detection of β-amyloid precursor protein(APP), p-tau, acetylcholine transferase(ChAT), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in small intestine. Real-time fluorescent quantitative polymerase chain reaction was used to detect the expression of α-syn, TH, beclin-1, microtubule-associated protein 1 light chain 3(LC3), and p62 mRNA and mmu-miR-99 a-5 p in the small intestine. The results of this study showed that, as compared with the model group, the number of activities, the expression levels of ChAT, TH, and p62 were significantly increased in the 3 MA group, the various piperine dose groups, and the medopar group(P<0.05), and their first foot licking time was shortened; APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were significantly reduced(P<0.05). However, as compared with the model group, the number of activities, ChAT, TH, and p62 expression levels in the rapamycin group were significantly reduced(P<0.05), and the APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were significantly increased(P<0.05). As compared with the 3 MA group, the number of activities, ChAT, TH, and p62 expression levels were significantly reduced in the low and medium dose piperine groups and rapamycin group(P<0.05); howe-ver, their first foot licking time was significantly prolonged, APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were increased significantly(P<0.05). As compared with the medopar group, the number of activities, ChAT, TH, and p62 expression levels were significantly reduced in low dose piperine group and rapamycin group(P<0.05), but their first foot licking time was significantly extended, and APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were significantly increased(P<0.05). In addition, as compared with the normal group, the small intestinal epithelial cells of the model group and the rapamycin group were shed off a lot, with severe damages of intestinal mucosa as well as edema and shedding of the small intestine villi. After administration of the therapeutic interventions, the small intestinal epithelial cells of the 3 MA group, each dose group of piperine, and the medopa group were slightly damaged and the villi were slightly shed off. In summary, piperine has a protective effect on the small intestine of PDD model mice, showing reduced expression of mmu-miR-99 a-5 p, pro-inflammatory factors and autophagy factors, and the mechanism of slowing PDD pathological symptoms may be related to the inhibition of autophagy.
Subject(s)
Animals , Male , Mice , Alkaloids , Autophagy , Benzodioxoles , Dementia , Intestine, Small , Parkinson Disease , Piperidines , Polyunsaturated AlkamidesABSTRACT
The α-synuclein (SNCA) gene is a pathogenic gene identified in rare familial Parkinson Disease (PD). Recent studies highlight the role of DNA methylation in the pathogenesis of familial and sporadic PD. Hypomethylation in SNCAgene has been associated with increased SNCA gene expression and was observed in post mortem brains of patients with sporadic PD. This study was aimed at evaluating the effect of iron (II) chloride on SH-SY5Y cell models as pertain to cell death caused by oxidative stress, upregulation of SNCA gene expression and reduced SNCA gene methylation. Result obtained from LDH assay showed significant (p<0.05) evidence of cell death in treated cells as compared to the control sample. Analysis for SNCAgene quantification using RT-PCR showed significant increases in fold change. Cells treated with 1000μM of FeCl₂showed the highest fold change of 6.0 while cells treated with 250μM had the lowest fold change of 1.8. In DNA methylation assay using pyrosequencing, cells treated with varying concentrations of FeCl₂showed significant (p<0.05) decrease in DNA methylation. At 250μM, 500μM and 750μM concentrations of FeCl₂, an average mean methylation levels of 1.84%, 1.40% and 1.23% was obtained respectively while cells treated with 1000μM had the lowest average mean methylation level of 1.0%. Thus, the decrease in methylation is linked to the upregulation of the SNCAgene which has been reported to be among the causative factors in the pathogenesis of Parkinson’s disease.
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Synucleinopathies are neurodegenerative disorders characterized by the progressive accumulation of α-synuclein (α-syn) in neurons and glia and include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this review, we consolidate our key findings and recent studies concerning the role of Toll-like receptor 2 (TLR2), a pattern recognition innate immune receptor, in the pathogenesis of synucleinopathies. First, we address the pathological interaction of α-syn with microglial TLR2 and its neurotoxic inflammatory effects. Then, we show that neuronal TLR2 activation not only induces abnormal α-syn accumulation by impairing autophagy, but also modulates α-syn transmission. Finally, we demonstrate that administration of a TLR2 functional inhibitor improves the neuropathology and behavioral deficits of a synucleinopathy mouse model. Altogether, we present TLR2 modulation as a promising immunotherapy for synucleinopathies.
Subject(s)
Animals , Mice , Autophagy , Dementia , Immunotherapy , Lewy Bodies , Neurodegenerative Diseases , Neuroglia , Neurons , Neuropathology , Parkinson Disease , Toll-Like Receptor 2 , Toll-Like ReceptorsABSTRACT
OBJECTIVE: To explore the effects of human A30P mutant α-synuclein (α-syn) on autophagy lysosome pathway and ubiquitin proteasome system. METHODS: Constructing stable cell lines expressing human A30P mutant α-syn in PC12 cells, and detecting the levels of autophagy related proteins LC3-II and p62 as well as ubiquitinated proteins. Furthermore, the influence of A30P mutant α-syn on cell viability upon normal and stress conditions was conducted by MTT assay. RESULTS: Expressing A30P mutant α-syn could significantly reduce autophagy related protein LC3-II level and increase level of autophagy substrate p62, as well as promote aggregation of ubiquitinated proteins. Otherwise, expressing A30P mutant α-syn did not reduce cell viability under normal conditions. However, cell viability was significantly reduced under treatment with neurotoxin rotenone or serum free condition in A30P mutant α-syn groups compared with empty vector group. CONCLUSION: Over expression of human A30P mutant α-syn could impair the protein degradation system and increase the sensitivity of cells to toxic insults.
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Objective • To investigate the effects of chaperone-mediated autophagy (CMA) on α-synuclein oligomers level in the Parkinson's disease (PD) cell model with impaired ubiquitin proteasome system (UPS). Methods • The PD cell model was established by adding the proteasome inhibitor lactacystin in the SK-N-SH cell line stably transfected with wild type α-synuclein. The levels of α-synuclein oligomers, lysosome-associated membrane protein type 2A (LAMP2A) and 70 kDa heat shock homologous protein (HSC70) were detected using Western blotting. CMA function was inhibited with LAMP2A siRNA, and its effects on α-synuclein oligomers and cell viability were detected. Furthermore, the interaction of LAMP2A with α-synuclein oligomers was detected by immunoprecipitation. Results • In the PD cell model, the levels of α-synuclein oligomers, and CMA related proteins, i.e. LAMP2A and HSC70, were increased. Inhibiting the expression of LAMP2A further increased α-synuclein oligomers level, while it decreased cell viability. Furthermore, LAMP2A could interact with α-synuclein oligomers. Conclusion • In the PD cell model, CMA is one of the pathways regulating α-synuclein oligomers level. Inhibiting CMA function can further increase the α-synuclein oligomers level and deteriorate cell survival.
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BACKGROUND/AIMS: α-Synucleinopathy in the brain is the neuropathological hallmark of Parkinson’s disease (PD). However, the functional impact of α-synucleinopathy in the enteric nervous system remains unknown. We aim to evaluate the association between gastrointestinal (GI) dysfunction and α-synuclein (αSYN) pathology in the stomach and colon of PD patients and controls, as well as to investigate the association between the αSYN pathology in GI tract and future PD risk. METHODS: A total of 35 PD patients and 52 neurologically intact subjects were enrolled in this study. Endoscopic biopsies were performed, and then immunohistochemical staining for αSYN was performed. All subjects completed the validated Rome III questionnaire for the assessment of GI symptoms. The association between GI symptoms and the αSYN pathology in GI mucosa was evaluated. Incident PD cases were assessed during a median follow-up of 46 months. RESULTS: The proportion of self-reported constipation and functional constipation through the Rome III questionnaire was significantly higher in PD patients than in controls (P 0.05). No incident PD cases were diagnosed during study period. CONCLUSIONS: Our present study suggests that the deposition of αSYN in the mucosal enteric nervous system may not be reflected by functional impairment of the affected segment of the gut.
Subject(s)
Humans , Biopsy , Brain , Colon , Constipation , Dyspepsia , Enteric Nervous System , Follow-Up Studies , Gastrointestinal Tract , Mucous Membrane , Parkinson Disease , Pathology , StomachABSTRACT
Hyperglycemia is one of the major risk factors for stroke. Hyperglycemia can lead to a more extensive infarct volume, aggravate neuronal damage after cerebral ischemia. α-Synuclein is especially abundant in neuronal tissue, where it underlies the etiopathology of several neurodegenerative diseases. This study investigated whether hyperglycemic conditions regulate the expression of α-synuclein in middle cerebral artery occlusion (MCAO)-induced cerebral ischemic injury. Male Sprague-Dawley rats were treated with streptozotocin (40 mg/kg) via intraperitoneal injection to induce hyperglycemic conditions. MCAO were performed four weeks after streptozotocin injection to induce focal cerebral ischemia, and cerebral cortex tissues were obtained 24 hours after MCAO. We confirmed that MCAO induced neurological functional deficits and cerebral infarction, and these changes were more extensive in diabetic animals compared to non-diabetic animals. Moreover, we identified a decrease in α-synuclein after MCAO injury. Diabetic animals showed a more serious decrease in α-synuclein than non-diabetic animals. Western blot and reverse-transcription PCR analyses confirmed more extensive decreases in α-synuclein expression in MCAO-injured animals with diabetic condition than these of non-diabetic animals. It is accepted that α-synuclein modulates neuronal cell death and exerts a neuroprotective effect. Thus, the results of this study suggest that hyperglycemic conditions cause more serious brain damage in ischemic brain injuries by decreasing α-synuclein expression.
Subject(s)
Animals , Humans , Male , alpha-Synuclein , Blotting, Western , Brain , Brain Injuries , Brain Ischemia , Cell Death , Cerebral Cortex , Cerebral Infarction , Hyperglycemia , Infarction, Middle Cerebral Artery , Injections, Intraperitoneal , Middle Cerebral Artery , Neurodegenerative Diseases , Neurons , Neuroprotective Agents , Polymerase Chain Reaction , Rats, Sprague-Dawley , Risk Factors , Streptozocin , StrokeABSTRACT
Parkinson disease(PD)is characterized by the loss of dopaminergic neurons in the substantia nigra and deposition of cytosolic inclusions in surviving neurons (Lewy bodies), resulting in motor deficits and non-motor symptoms.Although Levodopa remains the gold standard treatment for PD,side effects like dyskinesia followed by long-term use could notbe ignored.Consequently,there is a need for devel-opment new drugs. Baicalein is a flavonoid isolated from traditional Chinese herb, Scutellaria baicalensis Georgi.Our laboratory discovered that baicalein could effectively attenuate neurotoxicity of 6-hydroxy-dopamine(6-OHDA)and promote the differentiation of PC12 cells through high throughput drug screen-ing at the cellularlevel. In vivo studies have shown that baicalein exerts significant therapeutic effect, particularly in the attenuation of muscle tremor in 6-OHDA-lesioned rats.Based on the result from the so far acquired knowledge and previous findings from our laboratory, we could consider neuroprotec-tive mechanism of baicalein focus on the activities ofanti-oxidation and anti-inflammation. Baicalein could prevent oxidative stress and apoptosis through maintaining the mitochondrial function, inhibition of collapse of mitochondrial membrane potential, increase the activity of antioxidant enzymes and restraint of lipid peroxidation via several pathways such as Keap1/Nrf2/HO-1.Anti-inflammatory activity of baicalein exert by attenuating activation of astrocyte and microglia, as well as the production of cathepsin B and cytokines. Additionally, promoting the degradation of α-synuclein contributes to the neuroprotective effect of baicalein against Lewy bodies toxicity.Furthermore,baicalein also modulates the metabolic balance between glutamate(GLu)and gamma-aminobutyric acid(GABA).Overall,baica-lein could protect nervous systemby inhibiting oxidative damage and neuroinflammation caused by environmental and genetic factors.This article reviewed the developments of studies on pharmacody-namics and mechanism of baicalein in PD therapy and provideda reference for further exploration.