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1.
Takeshi Iwatsubo 《Neuropathology》2007,27(5):474-478
Lewy bodies (LBs) are hallmark lesions in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We raised a monoclonal antibody LB509 against purified LBs from the brains of patients with DLB that strongly immuolabled LBs, and found that α‐synuclein is one of the major components of LBs. Thus, the deposition of α‐synuclein, an abundant presynaptic brain protein, as fibrillary aggregates in affected neurons or glial cells, was highlighted as a hallmark lesion of a subset of neurodegenerative disorders, including PD, DLB and multiple system atrophy collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in and multiplication of α‐synuclein gene in some pedigrees of familial PD has strongly implicated α‐synuclein in the pathogenesis of PD and other synucleinopathies. We then examined the specific post‐translational modifications that characterize and underlie the aggregation of α‐synuclein in synucleinopathy brains by mass spectrometry and using a specific antibody, and found that serine 129 of α‐synuclein deposited in synucleinopathy lesions is selectively and extensively phosphorylated. Furthermore we generated transgenic C. elegans overexpressing α‐synuclein in neurons, and found that overexpression of familial PD‐linked mutant form of α‐synuclein impairs functions of dopamine neurons. These findings collectively underscore the importance of deposition of α‐synuclein as well as its phosphorylation in the pathogenesis of α‐synucleinopathies. 相似文献
2.
《Journal of neuroscience research》2017,95(9):1871-1887
The α‐synuclein protein exists in vivo in a variety of covalently modified and aggregated forms associated with Parkinson's disease (PD) pathology. However, the specific proteoform structures involved with neuropathological disease mechanisms are not clearly defined. Since α‐synuclein plays a role in presynaptic neurotransmitter release, an in vitro enzyme‐based assay was developed to measure glutamate release from mouse forebrain synaptoneurosomes (SNs) enriched in synaptic endings. Glutamate measurements utilizing SNs from various mouse genotypes (WT, over‐expressers, knock‐outs) suggested a concentration dependence of α‐synuclein on calcium/depolarization‐dependent presynaptic glutamate release from forebrain terminals. In vitro reconstitution experiments with recombinant human α‐synuclein proteoforms including monomers and aggregated forms (fibrils, oligomers) produced further evidence of this functional impact. Notably, brief exogenous applications of fibrillated forms of α‐synuclein enhanced SN glutamate release but monomeric forms did not, suggesting preferential membrane penetration and toxicity by the aggregated forms. However, when applied to brain tissue sections just prior to homogenization, both monomeric and fibrillated forms stimulated glutamate release. Immuno‐gold and transmission electron microscopy (TEM) detected exogenous fibrillated α‐synuclein associated with numerous SN membranous structures including synaptic terminals. Western blots and immuno‐gold TEM were consistent with SN internalization of α‐synuclein. Additional studies revealed no evidence of gross disruption of SN membrane integrity or glutamate transporter function by exogenous α‐synuclein. Overall excitotoxicity, due to enhanced glutamate release in the face of either overexpressed monomeric α‐synuclein or extrasynaptic exposure to fibrillated α‐synuclein, should be considered as a potential neuropathological pathway during the progression of PD and other synucleinopathies. © 2017 Wiley Periodicals, Inc. 相似文献
3.
Overexpression of α‐synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis
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Juliana Yoshie Terashima Roberta Sessa Stilhano Priscila Totarelli Monteforte Gustavo José da Silva Pereira Sang Won Han Andrana Karla Calgarotto Yi‐Te Hsu Rodrigo Portes Ureshino Cláudia Bincoletto Soraya Soubhi Smaili 《Journal of neuroscience research》2018,96(1):160-171
α‐Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing α‐synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express α‐synuclein and regulate α‐synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild‐type α‐synuclein and its A30P and A53T mutants on autophagy and apoptosis. We observed that in immortalized astrocyte cell lines, overexpression of α‐synuclein proteins promotes the decrease of LC3‐II and the increase of p62 protein levels, suggesting the inhibition of autophagy. When these cells were treated with rotenone, there was a loss of mitochondrial membrane potential, especially in cells expressing mutant α‐synuclein. The level of this decrease was related to the toxicity of the mutants because they show a more intense and sustained effect. The decrease in autophagy and the mitochondrial changes in conjunction with parkin expression levels may sensitize astrocytes to apoptosis. 相似文献
4.
Phosphorylated α‐synuclein in the retina is a biomarker of Parkinson's disease pathology severity
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Isabel Ortuño‐Lizarán BSc Thomas G. Beach MD PhD Geidy E. Serrano PhD Douglas G. Walker PhD Charles H. Adler MD PhD Nicolás Cuenca PhD 《Movement disorders》2018,33(8):1315-1324
Background : PD patients often have visual alterations, for example, loss of visual acuity, contrast sensitivity or motion perception, and diminished electroretinogram responses. PD pathology is mainly characterized by the accumulation of pathological α‐synuclein deposits in the brain, but little is known about how synucleinopathy affects the retina. Objective : To study the correlation between α‐synuclein deposits in the retina and brain of autopsied subjects with PD and incidental Lewy body disease. Methods : We evaluated the presence of phosphorylated α‐synuclein in the retina of autopsied subjects with PD (9 subjects), incidental Lewy body disease (4 subjects), and controls (6 subjects) by immunohistochemistry and compared the retinal synucleinopathy with brain disease severity indicators. Results : Whereas controls did not show any phosphorylated α‐synuclein immunoreactivity in their retina, all PD subjects and 3 of 4 incidental Lewy body disease subjects had phosphorylated α‐synuclein deposits in ganglion cell perikarya, dendrites, and axons, some of them resembling brain Lewy bodies and Lewy neurites. The Lewy‐type synucleinopathy density in the retina significantly correlated with Lewy‐type synucleinopathy density in the brain, with the Unified Parkinson's disease pathology stage and with the motor UPDRS. Conclusion : These data suggest that phosphorylated α‐synuclein accumulates in the retina in parallel with that in the brain, including in early stages preceding development of clinical signs of parkinsonism or dementia. Therefore, the retina may provide an in vivo indicator of brain pathology severity, and its detection could help in the diagnosis and monitoring of disease progression. © 2018 International Parkinson and Movement Disorder Society 相似文献
5.
Oligomeric α‐synuclein and β‐amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases
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Stephanie M. Williams Philip Schulz Michael R. Sierks 《The European journal of neuroscience》2016,43(1):3-16
Oligomeric forms of α‐synuclein and β‐amyloid are toxic protein variants that are thought to contribute to the onset and progression of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. The detection of toxic variants in human cerebrospinal fluid (CSF) and blood has great promise for facilitating early and accurate diagnoses of these devastating diseases. Two hurdles that have impeded the use of these protein variants as biomarkers are the availability of reagents that can bind the different variants and a sensitive assay to detect their very low concentrations. We previously isolated antibody‐based reagents that selectively bind two different oligomeric variants of α‐synuclein and two of β‐amyloid, and developed a phage‐based capture enzyme‐linked immunosorbent assay (ELISA) with subfemtomolar sensitivity to quantify their presence. Here, we used these reagents to show that these oligomeric α‐synuclein variants are preferentially present in PD brain tissue, CSF and serum, and that the oligomeric β‐amyloid variants are preferentially present in AD brain tissue, CSF, and serum. Some AD samples also had α‐synuclein pathology and some PD samples also had β‐amyloid pathology, and, very intriguingly, these PD cases also had a history of dementia. Detection of different oligomeric α‐synuclein and β‐amyloid species is an effective method for identifying tissue, CSF and sera from PD and AD samples, respectively, and samples that also contained early stages of other protein pathologies, indicating their potential value as blood‐based biomarkers for neurodegenerative diseases. 相似文献
6.
Christian Wider MD Justus C. Dachsel PhD Alexandra I. Soto BS Michael G. Heckman MS Nancy N. Diehl BS Mei Yue MD Sarah Lincoln BSc Jan O. Aasly MD PhD Kristoffer Haugarvoll MD PhD John Q. Trojanowski MD PhD Spiridon Papapetropoulos MD PhD Deborah Mash PhD Alex Rajput FRCPC Ali H. Rajput FRCPC J. Mark Gibson MD Timothy Lynch MD Dennis W. Dickson MD Ryan J. Uitti MD Zbigniew K. Wszolek MD Matthew J. Farrer PhD Owen A. Ross PhD 《Movement disorders》2009,24(3):455-459
Genetic variation in fibroblast growth factor 20 (FGF20) has been associated with risk of Parkinson's disease (PD). Functional evidence suggested the T allele of one SNP, rs12720208 C/T, altered PD risk by increasing FGF20 and α‐synuclein protein levels. Herein we report our association study of FGF20 and PD risk in four patient‐control series (total: 1,262 patients and 1,881 controls), and measurements of FGF20 and α‐synuclein protein levels in brain samples (nine patients). We found no evidence of association between FGF20 variability and PD risk, and no relationship between the rs12720208 genotype, FGF20 and α‐synuclein protein levels. © 2009 Movement Disorder Society 相似文献
7.
Tau/α‐synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study
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Manuel Delgado‐Alvarado MD Belén Gago PhD Ana Gorostidi PhD Haritz Jiménez‐Urbieta MSc Rosalía Dacosta‐Aguayo PhD Irene Navalpotro‐Gómez MD Javier Ruiz‐Martínez MD PhD Alberto Bergareche MD José F. Martí‐Massó MD PhD Pablo Martínez‐Lage MD PhD Andrea Izagirre MHSc María C. Rodríguez‐Oroz MD PhD 《Movement disorders》2017,32(7):1066-1073
Background : No CSF or plasma biomarker has been validated for diagnosis or progression of PD. Objectives : To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. Methods : CSF levels of α‐synuclein, amyloid‐ß1‐42, total tau, and threonine‐181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin‐1ß, interleukin‐2, interleukin, interferon‐γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. Results : CSF levels of α‐synuclein, amyloid‐ß1‐42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α‐synuclein, phosphorylated tau/α‐synuclein, total tau/amyloid‐ß1‐42+α‐synuclein, and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α‐synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut‐off value of ≤ 0.71). Phosphorylated tau/α‐synuclein and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin‐6 levels were positively correlated with UPDRS‐I, ‐II, and ‐III scores. Conclusions : The CSF phosphorylated tau/α‐synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin‐6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society 相似文献
8.
Kazuto Tsukita Haruhi Sakamaki‐Tsukita Kanta Tanaka Toshihiko Suenaga Ryosuke Takahashi 《Movement disorders》2019,34(10):1452-1463
Previous studies that have investigated the potential of in vivo abnormal α‐synuclein deposits as a pathological biomarker for PD included few participants and reported different diagnostic accuracies. Here, we aimed to confirm the diagnostic value of in vivo α‐synuclein deposits in PD through a systematic review and meta‐analysis, with special emphasis on determining the tissue most suitable for examination and assessing whether anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibodies should be used. Databases were searched on December 30, 2018. We finally included 41 case‐control studies that examined in vivo tissue samples using anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibody in PD patients and controls. Using a univariate random‐effects model, pooled sensitivity and specificity (95% confidence interval) of anti‐native α‐synuclein antibody were 0.54 (0.49‐0.60) and 0.72 (0.68‐0.76) for the gastrointestinal tract and 0.76 (0.60‐0.89) and 0.60 (0.43‐0.74) for the skin. Pooled sensitivity and specificity (95% confidence interval) of anti‐phosphorylated α‐synuclein antibody were 0.43 (0.37‐0.48) and 0.82 (0.78‐0.86) for the gastrointestinal tract, 0.76 (0.69‐0.82) and 1.00 (0.98‐1.00) for the skin, 0.42 (0.26‐0.59) and 0.94 (0.84‐0.99) for the minor salivary glands, and 0.66 (0.51‐0.79) and 0.96 (0.86‐1.00) for the submandibular glands. Although ubiquitous heterogeneity between the included studies should be noted when interpreting our results, our analyses demonstrated the following: (1) in vivo α‐synuclein immunoreactivity has the potential as a pathological biomarker for PD; (2) anti‐phosphorylated α‐synuclein antibody consistently has higher specificity than anti‐native α‐synuclein antibody; and (3) skin biopsy examination using anti‐phosphorylated α‐synuclein antibody has the best diagnostic accuracy, although feasibility remains an important issue. © 2019 International Parkinson and Movement Disorder Society 相似文献
9.
Nomie Cresto Camille Gardier Francesco Gubinelli Marie‐Claude Gaillard Graldine Liot Andrew B. West Emmanuel Brouillet 《The European journal of neuroscience》2019,49(3):339-363
Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α‐synuclein and LRRK2 pathogenic mutations. While α‐synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual‐enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α‐synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α‐synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14‐3‐3s that may regulate α‐synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α‐synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD. 相似文献
10.
Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine‐producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD‐causing mutations in α‐synuclein and the presence of aggregated α‐synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of α‐synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and α‐synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified α‐synuclein aggregation in the SN, resulting in greater abundance of α‐synuclein oligomers and unique dopamine‐induced oligomeric conformations. Furthermore, disruption of the dopamine‐α‐synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known α‐synuclein and dopamine biology, review the evidence for α‐synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. © 2019 International Parkinson and Movement Disorder Society 相似文献
11.
Benjamin Dehay PhD Marta Martinez‐Vicente PhD Guy A. Caldwell PhD Kim A. Caldwell PhD Zhenyue Yue PhD Mark R. Cookson PhD Christine Klein MD PhD Miquel Vila MD PhD Erwan Bezard PhD 《Movement disorders》2013,28(6):725-732
Impairment of autophagy‐lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson's disease (PD). ALP alterations are observed in sporadic PD brains and in toxic and genetic rodent models of PD‐related neurodegeneration. In addition, PD‐linked mutations and post‐translational modifications of α‐synuclein impair its own lysosomal‐mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD‐related genes, such as leucine‐rich repeat kinase‐2 (LRRK2), parkin, and phosphatase and tensin homolog (PTEN)‐induced putative kinase 1 (PINK1), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal‐related genes, such as glucocerebrosidase (GBA) and lysosomal type 5 P‐type ATPase (ATP13A2), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, α‐synuclein accumulation, and neurotoxicity. First, PD‐related GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to α‐synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum‐Golgi to lysosomes, leading to neurodegeneration. Second, PD‐related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to α‐synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease‐modifying therapeutic strategies aimed at restoring lysosomal levels and function. © 2013 Movement Disorder Society 相似文献
12.
Nathalie Dutheil PhD Qin Li PhD Matthias Klugmann PhD Wassilios G. Meissner MD PhD Pierre‐Olivier Fernagut PhD 《Movement disorders》2017,32(8):1230-1239
Background : MSA is a fatal neurodegenerative disorder characterized by a combination of autonomic dysfunction, cerebellar ataxia, and l ‐dopa unresponsive parkinsonism. The hallmark of MSA is the accumulation of α‐synuclein, forming cytoplasmic inclusions in oligodendrocytes. Adeno‐associated viruses allow efficient targeting of disease‐associated genes in selected cellular ensembles and have proven efficient for the neuronal overexpression of α‐synuclein in the substantia nigra in the context of PD. Objectives : We aimed to develop viral‐based models of MSA. Methods : Chimeric viral vectors expressing either human wild‐type α‐synuclein or green fluorescent protein under the control of mouse myelin basic protein were injected in the striatum of rats and monkeys. Rats underwent a longitudinal motor assessment before histopathological analysis at 3 and 6 months. Results : Injection of vectors expressing α‐synuclein in the striatum resulted in >80% oligodendroglial selectivity in rats and >60% in monkeys. Rats developed progressive motor deficits that were l ‐dopa unresponsive when assessed at 6 months. Significant loss of dopaminergic neurons occurred at 3 months, further progressing at 6 months, together with a loss of striatal neurons. Prominent α‐synuclein accumulation, including phosphorylated and proteinase‐K–resistant α‐synuclein, was detected in the striatum and substantia nigra. Conclusions : Viral‐mediated oligodendroglial expression of α‐synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how α‐synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies. © 2017 International Parkinson and Movement Disorder Society 相似文献
13.
Gabor G. Kovacs MD PhD Ivan J. Milenkovic cand med Matthias Preusser MD Herbert Budka MSc Dhc 《Movement disorders》2008,23(11):1608-1612
Aggregated α‐synuclein is the hallmark of Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA). Physiologically, α‐synuclein ensures normal functions of dopamine transporter (DAT) and tyrosine hydoxylase. In α‐synucleinopathies, it accumulates in neuronal cytoplasm and neurites through several stages. It is unclear whether the accumulation of pathological α‐synuclein in the substantia nigra in PD correlates with the dopaminergic deficit in the striatal target. We evaluated the impact of the nigral burden of pathological α‐synuclein immunoreactivity in 27 α‐synucleinopathy brains by morphometric immunohistochemistry. DAT immunoreactivity in the striatum inversely correlates with the total α‐synuclein burden in the substantia nigra but not with cytoplasmic inclusion counts only. This result has implications for imaging, clinicopathological correlative studies, and staging of the disease process. © 2008 Movement Disorder Society 相似文献
14.
Dale F. Sharrad Wei‐Ping Gai Simon J.H. Brookes 《The Journal of comparative neurology》2013,521(11):2523-2537
Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies and neurites composed mainly of the presynaptic protein α‐synuclein. Frequently, Lewy bodies and neurites are identified in the gut of Parkinson's disease patients and may underlie associated gastrointestinal dysfunctions. We recently reported selective expression of α‐synuclein in the axons of cholinergic neurons in the guinea pig and human distal gut; however, it is not clear whether α‐synuclein expression varies along the gut, nor how closely expression is associated with other synaptic proteins. We used multiple‐labeling immunohistochemistry to quantify which neurons in the guinea pig ileum expressed α‐synuclein, cysteine string protein‐α (CSPα), synaptophysin, synaptotagmin‐1, or synaptobrevin‐2 in their axons. Among the 10 neurochemically defined axonal populations, a significantly greater proportion of vesicular acetylcholine transporter‐immunoreactive (VAChT‐IR) varicosities (80% ± 1.7%, n = 4, P < 0.001) contained α‐synuclein immunoreactivity, and a significantly greater proportion of α‐synuclein‐IR axons also contained VAChT immunoreactivity (78% ± 1.3%, n = 4) compared with any of the other nine populations (P < 0.001). Among synaptophysin‐, synaptotagmin‐1‐, synaptobrevin‐2‐, and CSPα‐IR varicosities, 98% ± 0.7%, 96% ± 0.7%, 88% ± 1.6%, and 85% ± 2.9% (n = 4) contained α‐synuclein immunoreactivity, respectively. Among α‐synuclein‐IR varicosities, 96% ± 0.9%, 99% ± 0.6%, 83% ± 1.9%, and 87% ± 2.3% (n = 4) contained synaptophysin‐, synaptotagmin‐1‐, synaptobrevin‐2‐, and CSPα immunoreactivity, respectively. We report a close association between the expression of α‐synuclein and the expression of other synaptic proteins in cholinergic axons in the guinea pig ileum. Selective expression of α‐synuclein may relate to the neurotransmitter system utilized and predispose cholinergic enteric neurons to degeneration in Parkinson's disease. J. Comp. Neurol. 521:2523–2537, 2013. © 2013 Wiley Periodicals, Inc. 相似文献
15.
Lisa Fellner Regina Irschick Kathrin Schanda Markus Reindl Lars Klimaschewski Werner Poewe Gregor K. Wenning Nadia Stefanova 《Glia》2013,61(3):349-360
Alpha‐synucleinopathies (ASP) are neurodegenerative disorders, characterized by accumulation of misfolded α‐synuclein, selective neuronal loss, and extensive gliosis. It is accepted that microgliosis and astrogliosis contribute to the disease progression in ASP. Toll‐like receptors (TLRs) are expressed on cells of the innate immune system, including glia, and TLR4 dysregulation may play a role in ASP pathogenesis. In this study we aimed to define the involvement of TLR4 in microglial and astroglial activation induced by different forms of α‐synuclein (full length soluble, fibrillized, and C‐terminally truncated). Purified primary wild type (TLR4+/+) and TLR4 deficient (TLR4?/?) murine microglial and astroglial cell cultures were treated with recombinant α‐synuclein and phagocytic activity, NFκB nuclear translocation, cytokine release, and reactive oxygen species (ROS) production were measured. We show that TLR4 mediates α‐synuclein‐induced microglial phagocytic activity, pro‐inflammatory cytokine release, and ROS production. TLR4?/? astroglia present a suppressed pro‐inflammatory response and decreased ROS production triggered by α‐synuclein treatment. However, the uptake of α‐synuclein by primary astroglia is not dependent on TLR4 expression. Our results indicate the C‐terminally truncated form as the most potent inductor of TLR4‐dependent glial activation. The current findings suggest that TLR4 plays a modulatory role on glial pro‐inflammatory responses and ROS production triggered by α‐synuclein. In contrast to microglia, the uptake of alpha‐synuclein by astroglia is not dependent on TLR4. Our data provide novel insights into the mechanisms of α‐synuclein‐induced microglial and astroglial activation which may have an impact on understanding the pathogenesis of ASP. © 2012 Wiley Periodicals, Inc. 相似文献
16.
Katsutoshi Taguchi Yoshihisa Watanabe Atsushi Tsujimura Masaki Tanaka 《The Journal of comparative neurology》2016,524(6):1236-1258
α‐Synuclein, the major constituent of Lewy bodies (LBs), is normally expressed in presynapses and is involved in synaptic function. Abnormal intracellular aggregation of α‐synuclein is observed as LBs and Lewy neurites in neurodegenerative disorders, such as Parkinson's disease (PD) or dementia with Lewy bodies. Accumulated evidence suggests that abundant intracellular expression of α‐synuclein is one of the risk factors for pathological aggregation. Recently, we reported differential expression patterns of α‐synuclein between excitatory and inhibitory hippocampal neurons. Here we further investigated the precise expression profile in the adult mouse brain with special reference to vulnerable regions along the progression of idiopathic PD. The results show that α‐synuclein was highly expressed in the neuronal cell bodies of some early PD‐affected brain regions, such as the olfactory bulb, dorsal motor nucleus of the vagus, and substantia nigra pars compacta. Synaptic expression of α‐synuclein was mostly accompanied by expression of vesicular glutamate transporter‐1, an excitatory presynaptic marker. In contrast, expression of α‐synuclein in the GABAergic inhibitory synapses was different among brain regions. α‐Synuclein was clearly expressed in inhibitory synapses in the external plexiform layer of the olfactory bulb, globus pallidus, and substantia nigra pars reticulata, but not in the cerebral cortex, subthalamic nucleus, or thalamus. These results suggest that some neurons in early PD‐affected human brain regions express high levels of perikaryal α‐synuclein, as happens in the mouse brain. Additionally, synaptic profiles expressing α‐synuclein are different in various brain regions. J. Comp. Neurol. 524:1236–1258, 2016. © 2015 Wiley Periodicals, Inc. 相似文献
17.
Genetic mutations associated with α‐synuclein (α‐Syn) are implicated in the pathogenesis of Parkinson's disease (PD). PD is primarily a movement disorder, but patients are known to experience anxiety and other mood disorders. In this study, we examined the effect of the hA53T mutation during development by analyzing the protein expression of norepinephrine (NET), serotonin (SERT), and dopamine (DAT) transporters in addition to assessing locomotor and anxiety‐like behavior. We observed significant decreases in DAT expression at 8 months in transgenic animals compared with normal and younger mice. We used the elevated plus maze, open‐field test, and rotarod apparatus to evaluate wild‐type and hA53T hemizygous mice at 2, 8, and 12 months of age. Our results showed that 12‐month‐old transgenic mice spend more time in the open arms and display a greater number of open entries of the elevated plus maze compared with wild‐type controls and younger mice. Open‐field test results showed that 12‐month‐old mice travel a greater distance overall and travel more in the inner zone than either wild‐type or younger mice. Rotarod testing showed that 8‐ and 12‐month‐old transgenic mice perform better than either wild‐type controls or younger mice. Overall, 8–12‐month‐old transgenic mice showed a trend toward reduced anxiety‐like behavior and increased hyperactivity. These results indicate a possible role of the A53T α‐Syn mutation in anxiety‐like and hyperactive behaviors in a PD mouse model, suggesting that these behaviors might be comorbid with this disease. © 2010 Wiley‐Liss, Inc. 相似文献
18.
Lysosomal Dysfunction and α‐Synuclein Aggregation in Parkinson's Disease: Diagnostic Links
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Tim Moors MSc Silvia Paciotti PhD Davide Chiasserini PhD Paolo Calabresi MD Lucilla Parnetti MD PhD Tommaso Beccari PhD Wilma D. J. van de Berg PhD 《Movement disorders》2016,31(6):791-801
Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy–lysosomal system is involved in the intralysosomal hydrolysis of dysfunctional proteins, lysosomal impairment may contribute to α‐synuclein aggregation in PD. The degradation of α‐synuclein is a complex process involving different proteolytic mechanisms depending on protein burden, folding, posttranslational modifications, and yet unknown factors. In this review, evidence for lysosomal dysfunction in PD and its intimate relationship with α‐synuclein aggregation are discussed, after which the question of whether lysosomal proteins may serve as diagnostic biomarkers for PD is addressed. Changes in lysosomal enzymes, such as reduced glucocerebrosidase and cathepsin levels, have been observed in affected brain regions in PD patients. The detection of lysosomal proteins in CSF may provide a read‐out of lysosomal dysfunction in PD and holds promise for the development of diagnostic PD biomarkers. Initial PD biomarker studies demonstrated altered lysosomal enzyme activities in CSF of PD patients when compared with controls. However, CSF lysosomal enzyme activities alone could not discriminate between PD patients and controls. The combination of CSF lysosomal markers with α‐synuclein species and indicators of mitochondrial dysfunction, inflammation, and other pathological proteins in PD may be able to facilitate a more accurate diagnosis of PD. Further CSF biomarker studies are needed to investigate the utility of CSF lysosomal proteins as measures of disease state and disease progression in PD. © 2016 International Parkinson and Movement Disorder Society 相似文献
19.
Lysosomal‐associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease
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Karen E. Murphy PhD Amanda M. Gysbers BBTEC Sarah K. Abbott PhD Adena S. Spiro BSc MSc Akiko Furuta MD PhD Antony Cooper PhD Brett Garner PhD Tomohiro Kabuta PhD Glenda M. Halliday PhD 《Movement disorders》2015,30(12):1639-1647
Lysosomes are the primary catabolic compartment for the degradation of intracellular proteins through autophagy. The presence of abnormal intracellular α‐synuclein‐positive aggregates in Parkinson's disease (PD) indicates that the degradative capacity of lysosomes is impaired in PD. Specific dysfunction of chaperone‐mediated autophagy (CMA) in PD is suggested by reductions in the CMA membrane receptor, lysosomal‐associated membrane protein (LAMP) 2A, although whether LAMP2A is the only LAMP2 isoform affected by PD is unknown. Messenger RNA (mRNA) and protein expression of all three LAMP2 isoforms was assessed in brain extracts from regions with and without PD‐related increases in α‐synuclein in autopsy samples from subjects in the early pathological stage of PD (n = 9), compared to age‐ and postmortem delay‐matched controls (n = 10). In the early stages of PD, mRNA expression of all LAMP2 isoforms was not different from controls, with LAMP2B and LAMP2C protein levels also unchanged in PD. The selective loss of LAMP2A protein directly correlated with the increased levels of α‐synuclein and decreased levels of the CMA chaperone heat shock cognate protein 70 in the same PD samples, as well as with the accumulation of cytosolic CMA substrate proteins. Our data show that LAMP2 protein isoforms are differentially affected in the early stages of PD, with LAMP2A selectively reduced in association with increased α‐synuclein, and suggests that dysregulation of CMA‐mediated protein degradation occurs before substantial α‐synuclein aggregation in PD. © 2015 International Parkinson and Movement Disorder Society. 相似文献
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Dale F. Sharrad Elsbeth de Vries Simon J.H. Brookes 《The Journal of comparative neurology》2013,521(3):657-676
Parkinson's disease is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. The hallmark pathological features of Parkinson's disease are Lewy bodies and neurites, of which aggregated α‐synuclein is a major constituent. Frequently, Lewy pathology is identified in the distal gut of constipated Parkinson's disease patients. The neurons that innervate the distal gut that express α‐synuclein have not been identified. We used multiple‐labeling immunohistochemistry and anterograde tracing to quantify which neurons projecting to the guinea pig rectum and human colon expressed α‐synuclein in their axons. α‐Synuclein‐immunoreactivity was present in 24 ± 0.7% of somatostatin (SOM)‐immunoreactive (IR) varicosities; 20 ± 4.3% of substance P (SP)‐IR varicosities and 9 ± 1.3% vasoactive intestinal polypeptide (VIP)‐IR varicosities in guinea pig rectal myenteric ganglia. However, α‐synuclein‐immunoreactivity was localized in significantly more vesicular acetylcholine transporter (VAChT)‐IR varicosities (88 ± 3%, P < 0.001). Of SOM‐IR, SP‐IR, and VIP‐IR varicosities that lacked VAChT‐immunoreactivity, only 1 ± 0.3%, 0 ± 0.3%, and 0% contained α‐synuclein‐immunoreactivity, respectively. 71 ± 0.8% of VAChT‐IR varicosities in myenteric ganglia of human colon were α‐synuclein‐IR. In guinea pig rectal myenteric ganglia, α‐synuclein‐ and VAChT‐immunoreactivity coexisted in 15 ± 1.4% of biotinamide‐labeled extrinsic varicosities; only 1 ± 0.3% of biotinamide‐labeled extrinsic varicosities contained α‐synuclein‐immunoreactivity without VAChT‐immunoreactivity. α‐Synuclein expression in axons to the distal gut correlates closely with expression of the cholinergic marker, VAChT. This is the first report of cell‐selective α‐synuclein expression in the nervous system. Our results suggest cholinergic neurons in the gut may be vulnerable in Parkinson's disease. J. Comp. Neurol. 521:657–676, 2013. © 2012 Wiley Periodicals, Inc. 相似文献