The objective of the study was to explore the relationship between the indicators of Alzheimer’s disease and dementia with Lewy bodies using the voxel-based specific regional analysis system for Alzheimer’s Disease ...The objective of the study was to explore the relationship between the indicators of Alzheimer’s disease and dementia with Lewy bodies using the voxel-based specific regional analysis system for Alzheimer’s Disease (VSRAD) advance. Among 36 patients with suspected dementia, patients with Alzheimer’s disease and dementia with Lewy bodies were identified using VSRAD advance from March 1 to October 30, 2019. All patients underwent brain Magnetic Resonance Imaging (MRI). We diagnosed Alzheimer’s disease using Volume of Interest (VOI) in the Medial Temporal Lobe (MTL) atrophy ratio > 2 and dementia with Lewy bodies using both VOI in the MTL atrophy ratio ≤ 2 and gray/white matter atrophy ratio ≥ 0.2. The correlation between the indicators of Alzheimer’s disease and dementia with Lewy bodies was calculated. The number of patients classified as having Alzheimer’s disease and dementia with Lewy bodies was 25 and 11, respectively. In the Alzheimer’s disease group, the correlation coefficient between the extent of gray matter atrophy and the severity of atrophy in the dorsal brainstem gray matter was r = -0.40 (p = 0.045). In dementia with Lewy bodies group, the correlation coefficient between the extent of gray matter atrophy and the severity of atrophy in the dorsal brainstem white matter was r = -0.78 (p < 0.01). Using VSRAD advance, gray matter atrophy and dorsal brainstem grey/white matter atrophy were found to be negatively correlated in Alzheimer’s disease and dementia with Lewy bodies.展开更多
α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and...α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and highly phospho rylated a-synuclein constitutes the main component of Lewy bodies in the brain,the pathological hallmark of Parkinson s disease.For decades,much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson s disease as a systemic disease.Recent evidence demonstrates that,at least in some patients,the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain.Injection of α-synuclein preformed fibrils into the gastrointestinal tra ct trigge rs the gutto-brain propagation of α-synuclein pathology.However,whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation.In this review,we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson’s disease.We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.展开更多
Abnormal accumulation ofα-synuclein contributes to the formation of Lewy bodies in the substantia nigra,which is considered the typical pathological hallmark of Parkinson's disease.Recent research indicates that ...Abnormal accumulation ofα-synuclein contributes to the formation of Lewy bodies in the substantia nigra,which is considered the typical pathological hallmark of Parkinson's disease.Recent research indicates that angiotensin-(1-7)plays a crucial role in several neurodegenerative disorders,including Parkinson's disease,but the underlying mechanisms remain elusive.In this study,we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson's disease model.We investigated whether angiotensin-(1-7)is neuroprotective in this model by continuous administration of angiotensin-(1-7)into the right substantia nigra for 4 weeks.We found that angiotensin-(1-7)infusion relieved characteristic parkinsonian behaviors and reducedα-synuclein aggregation in the substantia nigra.Primary dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone,angiotensin-(1-7),and/or the Mas receptor blocker A-779 for 24 hours.After binding to the Mas receptor,angiotensin-(1-7)attenuated apoptosis andα-synuclein aggregation in rotenone-treated cells.Primary dopaminergic neurons were also treated with angiotensin-(1-7)and/or the autophagy inhibitor 3-methyladenine for 24 hours.Angiotensin-(1-7)increasedα-synuclein removal and increased the autophagy of rotenone-treated cells.We conclude that angiotensin-(1-7)reducesα-synuclein aggregation by alleviating autophagy dysfunction in Parkinson's disease.Therefore,the angiotensin-(1-7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson's disease and angiotensin-(1-7)has potential therapeutic value for Parkinson's disease.All experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital(approval No.DWSY-2000932)in January 2020.展开更多
Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular...Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.展开更多
Parkinson’s disease(PD)is one of the primary vital degenerative diseases that affect the Central Nervous System among elderly patients.It affect their quality of life drastically and millions of seniors are diagnosed...Parkinson’s disease(PD)is one of the primary vital degenerative diseases that affect the Central Nervous System among elderly patients.It affect their quality of life drastically and millions of seniors are diagnosed with PD every year worldwide.Several models have been presented earlier to detect the PD using various types of measurement data like speech,gait patterns,etc.Early identification of PD is important owing to the fact that the patient can offer important details which helps in slowing down the progress of PD.The recently-emerging Deep Learning(DL)models can leverage the past data to detect and classify PD.With this motivation,the current study develops a novel Colliding Bodies Optimization Algorithm with Optimal Kernel Extreme Learning Machine(CBO-OKELM)for diagnosis and classification of PD.The goal of the proposed CBO-OKELM technique is to identify whether PD exists or not.CBO-OKELM technique involves the design of Colliding Bodies Optimization-based Feature Selection(CBO-FS)technique for optimal subset of features.In addition,Water Strider Algorithm(WSA)with Kernel Extreme Learning Machine(KELM)model is also developed for the classification of PD.CBO algorithm is used to elect the optimal set of fea-tures whereas WSA is utilized for parameter tuning of KELM model which alto-gether helps in accomplishing the maximum PD diagnostic performance.The experimental analysis was conducted for CBO-OKELM technique against four benchmark datasets and the model portrayed better performance such as 95.68%,96.34%,92.49%,and 92.36%on Speech PD,Voice PD,Hand PD Mean-der,and Hand PD Spiral datasets respectively.展开更多
Both genetic and environmental factors are important in the pathogenesis of Parkinson's disease. As α-synuclein is a major constituent of Lewy bodies, a pathologic hallmark of Parkinson's disease, genetic aspects ...Both genetic and environmental factors are important in the pathogenesis of Parkinson's disease. As α-synuclein is a major constituent of Lewy bodies, a pathologic hallmark of Parkinson's disease, genetic aspects of α-synuclein is widely studied. However, the influence of dietary factors such as quercetin on α-synuclein was rarely studied. Herein we aimed to study the neuroprotective role of quercetin against various toxins affecting apoptosis, autophagy and aggresome, and the role of quercetin on α-synuclein expression. PC12 cells were pre-treated with quercetin(100, 500, 1,000 μM) and then together with various drugs such as 1-methyl-4-phenylpyridinium(MPP+; a free radical generator), 6-hydroxydopamine(6-OHDA; a free radical generator), ammonium chloride(an autophagy inhibitor), and nocodazole(an aggresome inhibitor). Cell viability was determined using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltertazolium bromide(MTT) assay. Apoptosis was detected by annexin V-fluorescein isothiocyanate and propidium iodide through the use of fluorescence activated cell sorter. α-Synuclein expression was detected by western blot assay and immunohistochemistry. The role of α-synuclein was further studied by knocking out α-synuclein using RNA interference. Cell viability increased at lower concentrations(100 and 500 μM) of quercetin but decreased at higher concentration(1,000 μM). Quercetin exerted neuroprotective effect against MPP+, ammonium chloride and nocodazole at 100 μM. MPP+ induced apoptosis was decreased by 100 μM quercetin. Quercetin treatment increased α-synuclein expression. However, knocking out α-synuclein exerted no significant effect on cell survival. In conclusion, quercetin is neuroprotective against toxic agents via affecting various mechanisms such as apoptosis, autophagy and aggresome. Because α-synuclein expression is increased by quercetin, the role of quercetin as an environmental factor in Parkinson's disease pathogenesis needs further investigation.展开更多
Parkinson’s disease (PD) is a heterogenous disease caused by multifactorial etiology. PD is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and the accumulation of Lewy bodies. In t...Parkinson’s disease (PD) is a heterogenous disease caused by multifactorial etiology. PD is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and the accumulation of Lewy bodies. In this study, two Drosophila PD models by exposing Drosophila to rotenone (sporadic PD models) are proposed, and the human α-synuclein A30P protein (family PD models) in Drosophila is expressed respectively. Both models recapitulated the main human PD symptoms including the loss of dopaminergic neurons in the brain and severe locomotor deficits. Our study finds that Rotenone induces more serious learning and memory impairment than α-synuclein A30P does.展开更多
It is well known that α-synuclein (αS) plays an important role in the pathogenesis of Parkinson’s disease (PD). Moreover, oxidative stress is also thought to be an important factor in PD due to induction of dopamin...It is well known that α-synuclein (αS) plays an important role in the pathogenesis of Parkinson’s disease (PD). Moreover, oxidative stress is also thought to be an important factor in PD due to induction of dopaminergic neuronal cell death by free radicals and enhancement of αS fibrillation by oxidized stress. In the present study, to clarify the role of glutathione (GSH), an intracellular antioxidant, on the molecular mechanism of αS-induced cell injury, we examined the effects of L-buthionine-SR-sulfoximine (BSO), a GSH synthase inhibitor, with or without N-acetyl-L-cysteine (NAC), a source of GSH, on αS-induced cell injury in human neuroblastoma SH-SY5Y cells. Treatment with BSO significantly reduced the cell viability of both empty-vector- and αS-transfected SH-SY5Y cells in a dose-dependent manner (p < 0.01), although the ratio of αS-induced reduction of cell viability in α-syn-transfected cells was much greater than that in empty-vector-transfected cells. Moreover, BSO significantly reduced the intracellular total GSH level in both types of transformant cells. However, NAC significantly prevented BSO-induced reduction of both cell viability and GSH level in the αS-transfected cells. These findings suggest that GSH plays an important role in αS-induced cell injury by reducing cell viability.展开更多
Background The accumulation ofα-synuclein(α-syn),an essential step in PD development and progression,is observed not only in neurons but also in glia,including astrocytes.The mechanisms regulating astrocyticα-syn l...Background The accumulation ofα-synuclein(α-syn),an essential step in PD development and progression,is observed not only in neurons but also in glia,including astrocytes.The mechanisms regulating astrocyticα-syn level and aggregation remain unclear.More recently,it has been demonstrated that a part ofα-syn spreading occurs through extracellular vesicles(EVs),although it is unknown whether this process is involved in astrocytes of PD.It is known,however,that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.Methods Primary astrocytes were transfected with A53Tα-syn plasmid or exposed toα-syn aggregates.The level of astrocyte-derived EVs(AEVs)was assessed by nanoparticle tracking analysis and immunofluorescence.The lysosomal function was evaluated by Cathepsin assays,immunofluorescence for levels of Lamp1 and Lamp2,and LysoTracker Red staining.The Apogee assays were optimized to measure the GLT-1+AEVs in clinical cohorts of 106 PD,47 multiple system atrophy(MSA),and 103 healthy control(HC)to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.Results The number of AEVs significantly increased in primary astrocytes withα-syn deposition.The mechanism of increased AEVs was partially attributed to lysosomal dysfunction.The number ofα-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA.The integrative model combining AEVs with total and aggregatedα-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915,and from MSA with an AUC of 0.877.Conclusions Pathologicalα-syn deposition could increase the astrocytic secretion of EVs,possibly throughα-syninduced lysosomal dysfunction.Theα-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.展开更多
Background:Abnormal aggregation of brainα-synuclein is a central step in the pathogenesis of Parkinson’s disease(PD),thus,it is reliable to promote the clearance ofα-synuclein to prevent and treat PD.Recent studies...Background:Abnormal aggregation of brainα-synuclein is a central step in the pathogenesis of Parkinson’s disease(PD),thus,it is reliable to promote the clearance ofα-synuclein to prevent and treat PD.Recent studies have revealed an essential role of glymphatic system and meningeal lymphatic vessels in the clearance of brain macromolecules,however,their pathophysiological aspects remain elusive.Method:Meningeal lymphatic drainage of 18-week-old A53T mice was blocked via ligating the deep cervical lymph nodes.Six weeks later,glymphatic functions and PD-like phenotypes were systemically analyzed.Results:Glymphatic influx of cerebrospinal fluid tracer was reduced in A53T mice,accompanied with perivascular aggregation ofα-synuclein and impaired polarization of aquaporin 4 expression in substantia nigra.Cervical lymphatic ligation aggravated glymphatic dysfunction of A53T mice,causing more severe accumulation ofα-synuclein,glial activation,inflammation,dopaminergic neuronal loss and motor deficits.Conclusion:The results suggest that brain lymphatic clearance dysfunction may be an aggravating factor in PD pathology.展开更多
Background:Parkinson’s disease(PD)is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms.PD is characterized by intraneuronal accumulati...Background:Parkinson’s disease(PD)is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms.PD is characterized by intraneuronal accumulation of abnormalα-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of eitherα-synuclein,as in the case of Multiple System Atrophy(MSA)or tau,as in the case of Corticobasal Degeneration(CBD)and Progressive Supranuclear Palsy(PSP),in other disease-specific brain regions.Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization ofα-synuclein or tau aggregates in the brain.Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues,including receptor neurons of the olfactory mucosa(OM).Methods:We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion(RT-QuIC)assay for OM analysis.In particular,by using human recombinantα-synuclein as substrate of reaction,we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induceα-synuclein aggregation,and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP.Results:Our results showed that a significant percentage of MSA and PD samples inducedα-synuclein aggregation with high efficiency,but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect.Notably,the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination.Conclusions:Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities forα-synuclein.Additional studies are required for(i)estimating sensitivity and specificity of the technique and for(ii)evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms.RT-QuIC analyses of OM and cerebrospinal fluid(CSF)can be combined with the aim of increasing the overall diagnostic accuracy of these diseases,especially in the early stages.展开更多
Background:Erythrocytes are a major source of peripheralα-synuclein(α-Syn).The goal of the current investigation is to evaluate erythrocytic total,oligomeric/aggregated,and phosphorylatedα-Syn species as biomarkers...Background:Erythrocytes are a major source of peripheralα-synuclein(α-Syn).The goal of the current investigation is to evaluate erythrocytic total,oligomeric/aggregated,and phosphorylatedα-Syn species as biomarkers of Parkinson’s disease(PD).PD and healthy control blood samples were collected along with extensive clinical history to determine whether total,phosphorylated,or aggregatedα-Syn derived from erythrocytes(the major source of bloodα-Syn)are more promising and consistent biomarkers for PD than are freeα-Syn species in serum or plasma.Methods:Using newly developed electrochemiluminescence assays,concentrations of erythrocytic total,aggregated and phosphorylated at Ser129(pS129)α-Syn,separated into membrane and cytosolic components,were measured in 225 PD patients and 133 healthy controls and analyzed with extensive clinical measures.Results:The total and aggregatedα-Syn levels were significantly higher in the membrane fraction of PD patients compared to healthy controls,but without alterations in the cytosolic component.The pS129 level was remarkably higher in PD subjects than in controls in the cytosolic fraction,and to a lesser extent,higher in the membrane fraction.Combining age,erythrocytic membrane aggregatedα-Syn,and cytosolic pS129 levels,a model generated by using logistic regression analysis was able to discriminate patients with PD from neurologically normal controls,with a sensitivity and a specificity of 72 and 68%,respectively.Conclusions:These results suggest that total,aggregated and phosphorylatedα-Syn levels are altered in PD erythrocytes and peripheral erythrocyticα-Syn is a potential PD biomarker that needs further validation.展开更多
OBJECTIVE: To review the recent progresses on the studies of α -synuclein in the pathogenesis of Parkinson disease (PD) and look into the perspective of α -synuclein as a new therapy target. DATA SOURCES: To sea...OBJECTIVE: To review the recent progresses on the studies of α -synuclein in the pathogenesis of Parkinson disease (PD) and look into the perspective of α -synuclein as a new therapy target. DATA SOURCES: To search the literatures on the progresses of PD studies, especially on the structure, gene expression of α-synuclein and the pathogenesis of PD in Medline from January 1998 to February 2007. Search terms were "Parkinson's disease, α-synuclein" in English. STUDY SELECTION: Initial check the data and choose the original and review articles directly linked to the role of α-synuclein in PD pathogenesis and screening out indirectly discussing articles. Collect the full text and trace the quoting articles and the quoted articles. Only the latest reviews were chosen in Chinese articles. DATA EXTRACTION: There were 424 articles on α-synuclein and its role in the pathogenesis of PD and 43 articles directly related with α-synuclein were chosen among which 12 were reviews. DATA SYNTHESIS: α-synuclein is a kind of soluble protein expressed in pre-synapse in central nervous system encoded by gene in homologous chromosome 4q21. It has physiological function in modulating the stability of membrane and neural plasticity. There is a close relationship between gene mutation in α -synuclein and the pathogenesis of PD. Environmental and genetic factors can induce the misfolding of α-synuclein, and secondary structural change can result in oligomer formation which induces a series of cascade reaction to damage dopaminergic system subsequently. Cell and animal transgenic and non-transgenic models are established recently and the important role of α-synuclein in the pathogenesis both of familial and sporadic PD is confirmed. Studies reveal that inhibiting the aggregation of α-synuclein can prevent its neurotoxicity; gene parkin can intercept the cell death pathway triggered by the aggregation of α-synuclein in cytoplasm. CONCLUSION: Gene mutation ofα-synuclein and the impairment in its structure and function are important in the pathogenesis of PD. Intervention of the gene mutations and abnormal protein aggregation ofα-synuclein may be a new strategy for preventing and treating PD.展开更多
Parkinson's disease (PD) is pathologically characterized by the presence of α-synuclein (α-syn)-positive intra-cytoplasmic inclusions named Lewy bodies in the dopaminergic neurons of the substantia nigra. A ser...Parkinson's disease (PD) is pathologically characterized by the presence of α-synuclein (α-syn)-positive intra-cytoplasmic inclusions named Lewy bodies in the dopaminergic neurons of the substantia nigra. A series of morbid consequences are caused by pathologically high amounts or mutant forms of α-syn, such as defects of membrane trafficking and lipid metabolism. In this review, we consider evidence that both point mutation and overexpression of α-syn result in aberrant degradation in neurons and microglia, and this is associated with the autophagy-lysosome pathway and endosome-lysosome system, leading directly to pathological intracellular aggregation, abnormal externalization and re-internalization cycling (and, in turn, internalization and re-externalization), and exocytosis. Based on these pathological changes, an increasing number of researchers have focused on these new therapeutic targets, aiming at alleviating the pathological accumulation of α-syn and re-establishing normal degradation.展开更多
Background:Aberrant aggregation ofα-synuclein(α-syn)is a key pathological feature of Parkinson’s disease(PD),but the precise role of intestinalα-syn in the progression of PD is unclear.In a number of genetic Droso...Background:Aberrant aggregation ofα-synuclein(α-syn)is a key pathological feature of Parkinson’s disease(PD),but the precise role of intestinalα-syn in the progression of PD is unclear.In a number of genetic Drosophila models of PD,α-syn was frequently ectopically expressed in the neural system to investigate the pathobiology.Method:We investigated the potential role of intestinalα-syn in PD pathogenesis using a Drosophila model.Humanα-syn was overexpressed in Drosophila guts,and life span,survival,immunofluorescence and climbing were evalu-ated.Immunofluorescence,Western blotting and reactive oxygen species(ROS)staining were performed to assess the effects of intestinalα-syn on intestinal dysplasia.High‐throughput RNA and 16S rRNA gene sequencing,quantitative RT‐PCR,immunofluorescence,and ROS staining were performed to determine the underlying molecular mechanism.Results:We found that the intestinalα-syn alone recapitulated many phenotypic and pathological features of PD,including impaired life span,loss of dopaminergic neurons,and progressive motor defects.The intestine-derivedα-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ageing.Moreover,intestinal expression ofα-syn induced dysbiosis,while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of PD.Intestinalα-syn triggered ROS,and eventually led to the activation of the dual oxidase(DUOX)-ROS-Jun N-terminal Kinase(JNK)pathway.In addition,α-syn from both the gut and the brain synergized to accelerate the progression of PD.Conclusions:The intestinal expression ofα-syn recapitulates many phenotypic and pathologic features of PD,and induces dysbiosis that aggravates the pathology through the DUOX-ROS-JNK pathway in Drosophila.Our findings provide new insights into the role of intestinalα-syn in PD pathophysiology.展开更多
Parkinson’s disease is the second most common neurodegenerative disorder;it affects 1%of the population over the age of 65.The number of people with Parkinson’s disease is set to rapidly increase due to changing dem...Parkinson’s disease is the second most common neurodegenerative disorder;it affects 1%of the population over the age of 65.The number of people with Parkinson’s disease is set to rapidly increase due to changing demographics and there is an unmet clinical need for disease-modifying therapies.The pathological hallmarks of Parkinson’s disease are the progressive degeneration of dopaminergic neurons in the substantia nigra and their axons which project to the striatum,and the aggregation ofα-synuclein;these result in a range of debilitating motor and non-motor symptoms.The application of neurotrophic factors to protect and potentially regenerate the remaining dopaminergic neurons is a major area of research interest.However,this strategy has had limited success to date.Clinical trials of two well-known neurotrophic factors,glial cell line-derived neurotrophic factor and neurturin,have reported limited efficacy in Parkinson’s disease patients,despite these factors showing potent neurotrophic actions in animal studies.There is therefore a need to identify other neurotrophic factors that can protect againstα-synuclein-induced degeneration of dopaminergic neurons.The bone morphogenetic protein(BMP)family is the largest subgroup of the transforming growth factor-βsuperfamily of proteins.BMPs are naturally secreted proteins that play crucial roles throughout the developing nervous system.Importantly,many BMPs have been shown to be potent neurotrophic factors for dopaminergic neurons.Here we discuss recent work showing that transcripts for the BMP receptors and BMP2 are co-expressed with several key markers of dopaminergic neurons in the human substantia nigra,and evidence for downregulation of BMP2 expression at distinct stages of Parkinson’s disease.We also discuss studies that explored the effects of BMP2 treatment,in in vitro and in vivo models of Parkinson’s disease.These studies found potent effects of BMP2 on dopaminergic neurites,which is important given that axon degeneration is increasingly recognized as a key early event in Parkinson’s disease.Thus,the aim of this mini-review is to give an overview of the BMP family and the BMP-Smad signalling pathway,in addition to reviewing the available evidence demonstrating the potential of BMP2 for Parkinson’s disease therapy.展开更多
X-box-binding protein 1-transfected neural stem cells were transplanted into the right lateral ventricles of rats with rotenone-induced Parkinson's disease. The survival capacities and differentiation rates of cells ...X-box-binding protein 1-transfected neural stem cells were transplanted into the right lateral ventricles of rats with rotenone-induced Parkinson's disease. The survival capacities and differentiation rates of cells expressing the dopaminergic marker tyrosine hydroxylase were higher in X-box-binding protein 1-transfected neural stem cells compared to non-transfected cells. Moreover, dopamine and 3,4-dihydroxyphenylacetic acid levels in the substantia nigra were significantly increased, α-synuclein expression was decreased, and neurological behaviors were significantly ameliorated in rats following transplantation of X-box-binding protein 1-transfected neural stem cells. These results indicate that transplantation of X-box-binding protein 1-transfected neural stem cells can promote stem cell survival and differentiation into dopaminergic neurons, increase dopamine and 3,4-dihydroxyphenylacetic acid levels, reduce α-synuclein aggregation in the substantia nigra, and improve the symptoms of Parkinson's disease in rats.展开更多
Parkinson’s disease(PD)is a common neurodegenerative disease,characterized clinically by both motor and non-motor symptoms.Pathologically,PD is hallmarked by the loss of dopaminergic neurons in the substantia nigra(S...Parkinson’s disease(PD)is a common neurodegenerative disease,characterized clinically by both motor and non-motor symptoms.Pathologically,PD is hallmarked by the loss of dopaminergic neurons in the substantia nigra(SN)and the formation ofα-synuclein(α-syn)containing inclusion bodies(Lewy pathology)in the surviving neurons.Diagnosis of PD is still based on clinical features.However,owing to the complexity,heterogeneity,and overlapping of its symptoms with other Parkinsonian disorders,correct diagnosis of PD remains a challenge,especially in the early stages.Therefore,there is an urgent need for biomarkers that can help correctly diagnose PD,differentiate PD from other Parkinsonian disorders,monitor the progression of the disease,and evaluate the therapeutic efficacy.Various molecules have been investigated for their utility in diagnosing PD,among whichα-syn is the most extensively investigated one due to its close implication in the etiology and pathogenesis of PD and related diseases.During the past decade,various species ofα-syn,including total,oligomeric,and phosphorylatedα-syn in various tissues,have been investigated for their utility as a potential biomarker for PD diagnosis and differential diagnosis.Various forms ofα-syn in body fluids,including cerebrospinal fluid(CSF),blood plasma,and saliva,are among the ones that are extensively investigated,since the body fluids are relatively accessible compared to the peripheral tissues.The aim of this review is to summarize the progress of studies on the utility ofα-syn in body fluid as a biomarker for PD diagnosis and differential diagnosis.展开更多
文摘The objective of the study was to explore the relationship between the indicators of Alzheimer’s disease and dementia with Lewy bodies using the voxel-based specific regional analysis system for Alzheimer’s Disease (VSRAD) advance. Among 36 patients with suspected dementia, patients with Alzheimer’s disease and dementia with Lewy bodies were identified using VSRAD advance from March 1 to October 30, 2019. All patients underwent brain Magnetic Resonance Imaging (MRI). We diagnosed Alzheimer’s disease using Volume of Interest (VOI) in the Medial Temporal Lobe (MTL) atrophy ratio > 2 and dementia with Lewy bodies using both VOI in the MTL atrophy ratio ≤ 2 and gray/white matter atrophy ratio ≥ 0.2. The correlation between the indicators of Alzheimer’s disease and dementia with Lewy bodies was calculated. The number of patients classified as having Alzheimer’s disease and dementia with Lewy bodies was 25 and 11, respectively. In the Alzheimer’s disease group, the correlation coefficient between the extent of gray matter atrophy and the severity of atrophy in the dorsal brainstem gray matter was r = -0.40 (p = 0.045). In dementia with Lewy bodies group, the correlation coefficient between the extent of gray matter atrophy and the severity of atrophy in the dorsal brainstem white matter was r = -0.78 (p < 0.01). Using VSRAD advance, gray matter atrophy and dorsal brainstem grey/white matter atrophy were found to be negatively correlated in Alzheimer’s disease and dementia with Lewy bodies.
基金supported by the National Natural Science Foundation of China,Nos.82271447,81771382the National Key Research and Development Program of China,No.2019 YFE0115900the"New 20 Terms of Universities in Jinan,No.202228022 (all to ZZ)。
文摘α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and highly phospho rylated a-synuclein constitutes the main component of Lewy bodies in the brain,the pathological hallmark of Parkinson s disease.For decades,much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson s disease as a systemic disease.Recent evidence demonstrates that,at least in some patients,the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain.Injection of α-synuclein preformed fibrils into the gastrointestinal tra ct trigge rs the gutto-brain propagation of α-synuclein pathology.However,whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation.In this review,we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson’s disease.We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.
基金supported by the National Natural Science Foundation of China,No.81801263(to QG)。
文摘Abnormal accumulation ofα-synuclein contributes to the formation of Lewy bodies in the substantia nigra,which is considered the typical pathological hallmark of Parkinson's disease.Recent research indicates that angiotensin-(1-7)plays a crucial role in several neurodegenerative disorders,including Parkinson's disease,but the underlying mechanisms remain elusive.In this study,we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson's disease model.We investigated whether angiotensin-(1-7)is neuroprotective in this model by continuous administration of angiotensin-(1-7)into the right substantia nigra for 4 weeks.We found that angiotensin-(1-7)infusion relieved characteristic parkinsonian behaviors and reducedα-synuclein aggregation in the substantia nigra.Primary dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone,angiotensin-(1-7),and/or the Mas receptor blocker A-779 for 24 hours.After binding to the Mas receptor,angiotensin-(1-7)attenuated apoptosis andα-synuclein aggregation in rotenone-treated cells.Primary dopaminergic neurons were also treated with angiotensin-(1-7)and/or the autophagy inhibitor 3-methyladenine for 24 hours.Angiotensin-(1-7)increasedα-synuclein removal and increased the autophagy of rotenone-treated cells.We conclude that angiotensin-(1-7)reducesα-synuclein aggregation by alleviating autophagy dysfunction in Parkinson's disease.Therefore,the angiotensin-(1-7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson's disease and angiotensin-(1-7)has potential therapeutic value for Parkinson's disease.All experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital(approval No.DWSY-2000932)in January 2020.
基金supported by the National Natural Science Foundation of China,No.82101340(to FJ).
文摘Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.
基金Taif University Researchers Supporting Project number(TURSP-2020/161),Taif University,Taif,Saudi Arabia.
文摘Parkinson’s disease(PD)is one of the primary vital degenerative diseases that affect the Central Nervous System among elderly patients.It affect their quality of life drastically and millions of seniors are diagnosed with PD every year worldwide.Several models have been presented earlier to detect the PD using various types of measurement data like speech,gait patterns,etc.Early identification of PD is important owing to the fact that the patient can offer important details which helps in slowing down the progress of PD.The recently-emerging Deep Learning(DL)models can leverage the past data to detect and classify PD.With this motivation,the current study develops a novel Colliding Bodies Optimization Algorithm with Optimal Kernel Extreme Learning Machine(CBO-OKELM)for diagnosis and classification of PD.The goal of the proposed CBO-OKELM technique is to identify whether PD exists or not.CBO-OKELM technique involves the design of Colliding Bodies Optimization-based Feature Selection(CBO-FS)technique for optimal subset of features.In addition,Water Strider Algorithm(WSA)with Kernel Extreme Learning Machine(KELM)model is also developed for the classification of PD.CBO algorithm is used to elect the optimal set of fea-tures whereas WSA is utilized for parameter tuning of KELM model which alto-gether helps in accomplishing the maximum PD diagnostic performance.The experimental analysis was conducted for CBO-OKELM technique against four benchmark datasets and the model portrayed better performance such as 95.68%,96.34%,92.49%,and 92.36%on Speech PD,Voice PD,Hand PD Mean-der,and Hand PD Spiral datasets respectively.
基金supported by a grant(03-2010-0240)from the Seoul National University Hospital Research Fund(BSJ)and Yuhan Cooperation(Seoul,Republic of KoreaTBA)
文摘Both genetic and environmental factors are important in the pathogenesis of Parkinson's disease. As α-synuclein is a major constituent of Lewy bodies, a pathologic hallmark of Parkinson's disease, genetic aspects of α-synuclein is widely studied. However, the influence of dietary factors such as quercetin on α-synuclein was rarely studied. Herein we aimed to study the neuroprotective role of quercetin against various toxins affecting apoptosis, autophagy and aggresome, and the role of quercetin on α-synuclein expression. PC12 cells were pre-treated with quercetin(100, 500, 1,000 μM) and then together with various drugs such as 1-methyl-4-phenylpyridinium(MPP+; a free radical generator), 6-hydroxydopamine(6-OHDA; a free radical generator), ammonium chloride(an autophagy inhibitor), and nocodazole(an aggresome inhibitor). Cell viability was determined using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltertazolium bromide(MTT) assay. Apoptosis was detected by annexin V-fluorescein isothiocyanate and propidium iodide through the use of fluorescence activated cell sorter. α-Synuclein expression was detected by western blot assay and immunohistochemistry. The role of α-synuclein was further studied by knocking out α-synuclein using RNA interference. Cell viability increased at lower concentrations(100 and 500 μM) of quercetin but decreased at higher concentration(1,000 μM). Quercetin exerted neuroprotective effect against MPP+, ammonium chloride and nocodazole at 100 μM. MPP+ induced apoptosis was decreased by 100 μM quercetin. Quercetin treatment increased α-synuclein expression. However, knocking out α-synuclein exerted no significant effect on cell survival. In conclusion, quercetin is neuroprotective against toxic agents via affecting various mechanisms such as apoptosis, autophagy and aggresome. Because α-synuclein expression is increased by quercetin, the role of quercetin as an environmental factor in Parkinson's disease pathogenesis needs further investigation.
基金supported by the Major State Basic Research and Development Program of China (Grant No.2006CB500702)the National Natural Science Foundation of China (Grant No.31070954)+1 种基金the Innovation Foundation of Shanghai Commission of Education Science and Technology (Grant No.08ZZ41)the Basic Research Foundation of Shanghai Commission of Science and Technology (Grant Nos.03JC14030,09JC1406600)
文摘Parkinson’s disease (PD) is a heterogenous disease caused by multifactorial etiology. PD is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and the accumulation of Lewy bodies. In this study, two Drosophila PD models by exposing Drosophila to rotenone (sporadic PD models) are proposed, and the human α-synuclein A30P protein (family PD models) in Drosophila is expressed respectively. Both models recapitulated the main human PD symptoms including the loss of dopaminergic neurons in the brain and severe locomotor deficits. Our study finds that Rotenone induces more serious learning and memory impairment than α-synuclein A30P does.
文摘It is well known that α-synuclein (αS) plays an important role in the pathogenesis of Parkinson’s disease (PD). Moreover, oxidative stress is also thought to be an important factor in PD due to induction of dopaminergic neuronal cell death by free radicals and enhancement of αS fibrillation by oxidized stress. In the present study, to clarify the role of glutathione (GSH), an intracellular antioxidant, on the molecular mechanism of αS-induced cell injury, we examined the effects of L-buthionine-SR-sulfoximine (BSO), a GSH synthase inhibitor, with or without N-acetyl-L-cysteine (NAC), a source of GSH, on αS-induced cell injury in human neuroblastoma SH-SY5Y cells. Treatment with BSO significantly reduced the cell viability of both empty-vector- and αS-transfected SH-SY5Y cells in a dose-dependent manner (p < 0.01), although the ratio of αS-induced reduction of cell viability in α-syn-transfected cells was much greater than that in empty-vector-transfected cells. Moreover, BSO significantly reduced the intracellular total GSH level in both types of transformant cells. However, NAC significantly prevented BSO-induced reduction of both cell viability and GSH level in the αS-transfected cells. These findings suggest that GSH plays an important role in αS-induced cell injury by reducing cell viability.
基金supported by the National Natural Science Foundation of China(82020108012,82001200,81571226 and 81671187)the Natural Science Foundation of Zhejiang Province(LZ23H090002)+1 种基金the Leading Innovation and Entrepreneurship Team in Zhejiang Province(2020R01001)Innovative Institute of Basic Medical Science of Zhejiang University.
文摘Background The accumulation ofα-synuclein(α-syn),an essential step in PD development and progression,is observed not only in neurons but also in glia,including astrocytes.The mechanisms regulating astrocyticα-syn level and aggregation remain unclear.More recently,it has been demonstrated that a part ofα-syn spreading occurs through extracellular vesicles(EVs),although it is unknown whether this process is involved in astrocytes of PD.It is known,however,that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.Methods Primary astrocytes were transfected with A53Tα-syn plasmid or exposed toα-syn aggregates.The level of astrocyte-derived EVs(AEVs)was assessed by nanoparticle tracking analysis and immunofluorescence.The lysosomal function was evaluated by Cathepsin assays,immunofluorescence for levels of Lamp1 and Lamp2,and LysoTracker Red staining.The Apogee assays were optimized to measure the GLT-1+AEVs in clinical cohorts of 106 PD,47 multiple system atrophy(MSA),and 103 healthy control(HC)to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.Results The number of AEVs significantly increased in primary astrocytes withα-syn deposition.The mechanism of increased AEVs was partially attributed to lysosomal dysfunction.The number ofα-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA.The integrative model combining AEVs with total and aggregatedα-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915,and from MSA with an AUC of 0.877.Conclusions Pathologicalα-syn deposition could increase the astrocytic secretion of EVs,possibly throughα-syninduced lysosomal dysfunction.Theα-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.
基金This work was supported by grants from the National Natural Science Foundation of China(81671070 and 81473196).
文摘Background:Abnormal aggregation of brainα-synuclein is a central step in the pathogenesis of Parkinson’s disease(PD),thus,it is reliable to promote the clearance ofα-synuclein to prevent and treat PD.Recent studies have revealed an essential role of glymphatic system and meningeal lymphatic vessels in the clearance of brain macromolecules,however,their pathophysiological aspects remain elusive.Method:Meningeal lymphatic drainage of 18-week-old A53T mice was blocked via ligating the deep cervical lymph nodes.Six weeks later,glymphatic functions and PD-like phenotypes were systemically analyzed.Results:Glymphatic influx of cerebrospinal fluid tracer was reduced in A53T mice,accompanied with perivascular aggregation ofα-synuclein and impaired polarization of aquaporin 4 expression in substantia nigra.Cervical lymphatic ligation aggravated glymphatic dysfunction of A53T mice,causing more severe accumulation ofα-synuclein,glial activation,inflammation,dopaminergic neuronal loss and motor deficits.Conclusion:The results suggest that brain lymphatic clearance dysfunction may be an aggravating factor in PD pathology.
基金This study was supported in part by the Italian Ministry of Health(GR-2013-02355724)the Michael J.Fox Foundation,Alzheimer’s Association,Alzheimer’s Research UK and the Weston Brain Institute(BAND 11035)+1 种基金Associazione Italiana Encefalopatie da Prioni(AIEnP)to FMItalian Ministry of Health(GR-2009-1607326)to AEE,Italian Ministry of Health(NET-2011-02346784)to FT and NIH/NIA(P30 AG10133)to Bernardino Ghetti.
文摘Background:Parkinson’s disease(PD)is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms.PD is characterized by intraneuronal accumulation of abnormalα-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of eitherα-synuclein,as in the case of Multiple System Atrophy(MSA)or tau,as in the case of Corticobasal Degeneration(CBD)and Progressive Supranuclear Palsy(PSP),in other disease-specific brain regions.Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization ofα-synuclein or tau aggregates in the brain.Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues,including receptor neurons of the olfactory mucosa(OM).Methods:We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion(RT-QuIC)assay for OM analysis.In particular,by using human recombinantα-synuclein as substrate of reaction,we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induceα-synuclein aggregation,and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP.Results:Our results showed that a significant percentage of MSA and PD samples inducedα-synuclein aggregation with high efficiency,but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect.Notably,the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination.Conclusions:Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities forα-synuclein.Additional studies are required for(i)estimating sensitivity and specificity of the technique and for(ii)evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms.RT-QuIC analyses of OM and cerebrospinal fluid(CSF)can be combined with the aim of increasing the overall diagnostic accuracy of these diseases,especially in the early stages.
基金This research was supported by the National Key Technology Research and Development Program of China(No.2016YFC1306500)National Institutes of Health(U01 NS082137 and U01 NS091272)+9 种基金Natural Science Foundation of China(No.81571226 and No.81671187)Beijing Municipal Science and Technology Commission(No.Z151100003915117,Z151100003915150)Beijing Natural Science Foundation(No.7164254)Beijing Science and Technology(Z161100000216150)National Key Technology Research and Development Program of China(No.2016YFC1306500)supported sample collection and ECL assay development and sample testingNational Institutes of Health(U01 NS082137 and U01 NS091272)supported data analysis and manuscript writingNatural Science Foundation of China(No.81571226 and No.81671187)supported cohort management and sample collectionBeijing Municipal Science and Technology Commission(No.Z151100003915117,Z151100003915150)supported cohort management and sample collectionBeijing Natural Science Foundation(No.7164254)Beijing Science and Technology(Z161100000216150)supported cohort management and sample collection.
文摘Background:Erythrocytes are a major source of peripheralα-synuclein(α-Syn).The goal of the current investigation is to evaluate erythrocytic total,oligomeric/aggregated,and phosphorylatedα-Syn species as biomarkers of Parkinson’s disease(PD).PD and healthy control blood samples were collected along with extensive clinical history to determine whether total,phosphorylated,or aggregatedα-Syn derived from erythrocytes(the major source of bloodα-Syn)are more promising and consistent biomarkers for PD than are freeα-Syn species in serum or plasma.Methods:Using newly developed electrochemiluminescence assays,concentrations of erythrocytic total,aggregated and phosphorylated at Ser129(pS129)α-Syn,separated into membrane and cytosolic components,were measured in 225 PD patients and 133 healthy controls and analyzed with extensive clinical measures.Results:The total and aggregatedα-Syn levels were significantly higher in the membrane fraction of PD patients compared to healthy controls,but without alterations in the cytosolic component.The pS129 level was remarkably higher in PD subjects than in controls in the cytosolic fraction,and to a lesser extent,higher in the membrane fraction.Combining age,erythrocytic membrane aggregatedα-Syn,and cytosolic pS129 levels,a model generated by using logistic regression analysis was able to discriminate patients with PD from neurologically normal controls,with a sensitivity and a specificity of 72 and 68%,respectively.Conclusions:These results suggest that total,aggregated and phosphorylatedα-Syn levels are altered in PD erythrocytes and peripheral erythrocyticα-Syn is a potential PD biomarker that needs further validation.
文摘OBJECTIVE: To review the recent progresses on the studies of α -synuclein in the pathogenesis of Parkinson disease (PD) and look into the perspective of α -synuclein as a new therapy target. DATA SOURCES: To search the literatures on the progresses of PD studies, especially on the structure, gene expression of α-synuclein and the pathogenesis of PD in Medline from January 1998 to February 2007. Search terms were "Parkinson's disease, α-synuclein" in English. STUDY SELECTION: Initial check the data and choose the original and review articles directly linked to the role of α-synuclein in PD pathogenesis and screening out indirectly discussing articles. Collect the full text and trace the quoting articles and the quoted articles. Only the latest reviews were chosen in Chinese articles. DATA EXTRACTION: There were 424 articles on α-synuclein and its role in the pathogenesis of PD and 43 articles directly related with α-synuclein were chosen among which 12 were reviews. DATA SYNTHESIS: α-synuclein is a kind of soluble protein expressed in pre-synapse in central nervous system encoded by gene in homologous chromosome 4q21. It has physiological function in modulating the stability of membrane and neural plasticity. There is a close relationship between gene mutation in α -synuclein and the pathogenesis of PD. Environmental and genetic factors can induce the misfolding of α-synuclein, and secondary structural change can result in oligomer formation which induces a series of cascade reaction to damage dopaminergic system subsequently. Cell and animal transgenic and non-transgenic models are established recently and the important role of α-synuclein in the pathogenesis both of familial and sporadic PD is confirmed. Studies reveal that inhibiting the aggregation of α-synuclein can prevent its neurotoxicity; gene parkin can intercept the cell death pathway triggered by the aggregation of α-synuclein in cytoplasm. CONCLUSION: Gene mutation ofα-synuclein and the impairment in its structure and function are important in the pathogenesis of PD. Intervention of the gene mutations and abnormal protein aggregation ofα-synuclein may be a new strategy for preventing and treating PD.
基金supported by the National Program of Basic Research of China(2010CB945200, 2011CB504104)the National Natural Science Foundation of China (30700888, 30770732,30872729, 30971031)+2 种基金the Key Discipline Program of Shanghai Municipality (S30202)the Shanghai Key Project of Basic Science Research (10411954500)the Program for Outstanding Medical Academic Leaders of Shanghai Municipality, China (LJ 06003)
文摘Parkinson's disease (PD) is pathologically characterized by the presence of α-synuclein (α-syn)-positive intra-cytoplasmic inclusions named Lewy bodies in the dopaminergic neurons of the substantia nigra. A series of morbid consequences are caused by pathologically high amounts or mutant forms of α-syn, such as defects of membrane trafficking and lipid metabolism. In this review, we consider evidence that both point mutation and overexpression of α-syn result in aberrant degradation in neurons and microglia, and this is associated with the autophagy-lysosome pathway and endosome-lysosome system, leading directly to pathological intracellular aggregation, abnormal externalization and re-internalization cycling (and, in turn, internalization and re-externalization), and exocytosis. Based on these pathological changes, an increasing number of researchers have focused on these new therapeutic targets, aiming at alleviating the pathological accumulation of α-syn and re-establishing normal degradation.
基金the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research(STaR)Investigator Award(NMRC/STaR/0030/2018)National Parkinson’s Disease Translational Clinical Research Programme(013-NNI/2014)+1 种基金National Medical Research Council Singapore,OF LCG 000207,SPARKS II,and Innovative Research Group Project of the the National Natural Science Foundation of China(31501175)Talents in Anhui Agricultural University(RC342201).
文摘Background:Aberrant aggregation ofα-synuclein(α-syn)is a key pathological feature of Parkinson’s disease(PD),but the precise role of intestinalα-syn in the progression of PD is unclear.In a number of genetic Drosophila models of PD,α-syn was frequently ectopically expressed in the neural system to investigate the pathobiology.Method:We investigated the potential role of intestinalα-syn in PD pathogenesis using a Drosophila model.Humanα-syn was overexpressed in Drosophila guts,and life span,survival,immunofluorescence and climbing were evalu-ated.Immunofluorescence,Western blotting and reactive oxygen species(ROS)staining were performed to assess the effects of intestinalα-syn on intestinal dysplasia.High‐throughput RNA and 16S rRNA gene sequencing,quantitative RT‐PCR,immunofluorescence,and ROS staining were performed to determine the underlying molecular mechanism.Results:We found that the intestinalα-syn alone recapitulated many phenotypic and pathological features of PD,including impaired life span,loss of dopaminergic neurons,and progressive motor defects.The intestine-derivedα-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ageing.Moreover,intestinal expression ofα-syn induced dysbiosis,while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of PD.Intestinalα-syn triggered ROS,and eventually led to the activation of the dual oxidase(DUOX)-ROS-Jun N-terminal Kinase(JNK)pathway.In addition,α-syn from both the gut and the brain synergized to accelerate the progression of PD.Conclusions:The intestinal expression ofα-syn recapitulates many phenotypic and pathologic features of PD,and induces dysbiosis that aggravates the pathology through the DUOX-ROS-JNK pathway in Drosophila.Our findings provide new insights into the role of intestinalα-syn in PD pathophysiology.
基金supported by a RISAM PhD Scholarship from Cork Institute of Technology(R00094948)a research grant from Science Foundation Ireland(SFI)under the grant number 15/CDA/3498(to GWOK)
文摘Parkinson’s disease is the second most common neurodegenerative disorder;it affects 1%of the population over the age of 65.The number of people with Parkinson’s disease is set to rapidly increase due to changing demographics and there is an unmet clinical need for disease-modifying therapies.The pathological hallmarks of Parkinson’s disease are the progressive degeneration of dopaminergic neurons in the substantia nigra and their axons which project to the striatum,and the aggregation ofα-synuclein;these result in a range of debilitating motor and non-motor symptoms.The application of neurotrophic factors to protect and potentially regenerate the remaining dopaminergic neurons is a major area of research interest.However,this strategy has had limited success to date.Clinical trials of two well-known neurotrophic factors,glial cell line-derived neurotrophic factor and neurturin,have reported limited efficacy in Parkinson’s disease patients,despite these factors showing potent neurotrophic actions in animal studies.There is therefore a need to identify other neurotrophic factors that can protect againstα-synuclein-induced degeneration of dopaminergic neurons.The bone morphogenetic protein(BMP)family is the largest subgroup of the transforming growth factor-βsuperfamily of proteins.BMPs are naturally secreted proteins that play crucial roles throughout the developing nervous system.Importantly,many BMPs have been shown to be potent neurotrophic factors for dopaminergic neurons.Here we discuss recent work showing that transcripts for the BMP receptors and BMP2 are co-expressed with several key markers of dopaminergic neurons in the human substantia nigra,and evidence for downregulation of BMP2 expression at distinct stages of Parkinson’s disease.We also discuss studies that explored the effects of BMP2 treatment,in in vitro and in vivo models of Parkinson’s disease.These studies found potent effects of BMP2 on dopaminergic neurites,which is important given that axon degeneration is increasingly recognized as a key early event in Parkinson’s disease.Thus,the aim of this mini-review is to give an overview of the BMP family and the BMP-Smad signalling pathway,in addition to reviewing the available evidence demonstrating the potential of BMP2 for Parkinson’s disease therapy.
文摘X-box-binding protein 1-transfected neural stem cells were transplanted into the right lateral ventricles of rats with rotenone-induced Parkinson's disease. The survival capacities and differentiation rates of cells expressing the dopaminergic marker tyrosine hydroxylase were higher in X-box-binding protein 1-transfected neural stem cells compared to non-transfected cells. Moreover, dopamine and 3,4-dihydroxyphenylacetic acid levels in the substantia nigra were significantly increased, α-synuclein expression was decreased, and neurological behaviors were significantly ameliorated in rats following transplantation of X-box-binding protein 1-transfected neural stem cells. These results indicate that transplantation of X-box-binding protein 1-transfected neural stem cells can promote stem cell survival and differentiation into dopaminergic neurons, increase dopamine and 3,4-dihydroxyphenylacetic acid levels, reduce α-synuclein aggregation in the substantia nigra, and improve the symptoms of Parkinson's disease in rats.
文摘Parkinson’s disease(PD)is a common neurodegenerative disease,characterized clinically by both motor and non-motor symptoms.Pathologically,PD is hallmarked by the loss of dopaminergic neurons in the substantia nigra(SN)and the formation ofα-synuclein(α-syn)containing inclusion bodies(Lewy pathology)in the surviving neurons.Diagnosis of PD is still based on clinical features.However,owing to the complexity,heterogeneity,and overlapping of its symptoms with other Parkinsonian disorders,correct diagnosis of PD remains a challenge,especially in the early stages.Therefore,there is an urgent need for biomarkers that can help correctly diagnose PD,differentiate PD from other Parkinsonian disorders,monitor the progression of the disease,and evaluate the therapeutic efficacy.Various molecules have been investigated for their utility in diagnosing PD,among whichα-syn is the most extensively investigated one due to its close implication in the etiology and pathogenesis of PD and related diseases.During the past decade,various species ofα-syn,including total,oligomeric,and phosphorylatedα-syn in various tissues,have been investigated for their utility as a potential biomarker for PD diagnosis and differential diagnosis.Various forms ofα-syn in body fluids,including cerebrospinal fluid(CSF),blood plasma,and saliva,are among the ones that are extensively investigated,since the body fluids are relatively accessible compared to the peripheral tissues.The aim of this review is to summarize the progress of studies on the utility ofα-syn in body fluid as a biomarker for PD diagnosis and differential diagnosis.