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1.
Stemberger S Wenning GK 《Journal of neural transmission (Vienna, Austria : 1996)》2011,118(5):841-847
Multiple system atrophy (MSA) is a fatal late-onset α-synucleinopathy that presents with features of ataxia, Parkinsonism,
and pyramidal dysfunction in any combination. Over the last decade, efforts have been made to develop preclinical MSA testbeds
for novel interventional strategies. The main focus has been on murine analogues of MSA-linked motor features and their underlying
brainstem, cerebellar and basal ganglia pathology. Although progressive autonomic failure (AF) is a prominent clinical feature
of patients with MSA, reflecting a disruption of both central and peripheral autonomic networks controlling cardiovascular,
respiratory, urogenital, gastrointestinal and sudomotor functions, attempts of modelling this aspect of the human disease
have been limited. However, emerging evidence suggests that AF-like features may occur in transgenic MSA models reflecting
α-synucleinopathy lesions in distributed autonomic networks. Further research is needed to fully characterize both autonomic
and motor features in optimized preclinical MSA models. 相似文献
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Prasad K Tarasewicz E Strickland PA O'Neill M Mitchell SN Merchant K Tep S Hilton K Datwani A Buttini M Mueller-Steiner S Richfield EK 《The European journal of neuroscience》2011,33(4):642-656
A consensus about the functions of human wild-type or mutated α-synuclein (αSYN) is lacking. Both forms of αSYN are implicated in Parkinson's disease, whereas the wild-type form is implicated in substance abuse. Interactions with other cellular proteins and organelles may meditate its functions. We developed a series of congenic mouse lines containing various allele doses or combinations of the human wild-type αSYN (hwαSYN) or a doubly mutated (A30P*A53T) αSYN (hm(2) αSYN) in a C57Bl/6J line spontaneously deleted in mouse αSYN (C57BL/6JOla). Both transgenes had a functional role in the nigrostriatal system, demonstrated by significant elevations in striatal catecholamines, metabolites and the enzyme tyrosine hydroxylase compared with null-mice without a transgene. Consequences occurred when the transgenes were expressed at a fraction of the endogenous level. Hemizygous congenic mice did not exhibit any change in the number or size of dopaminergic neurons in the ventral midbrain at 9 months of age. Human αSYN was predominantly located in neuronal cell bodies, neurites, synapses, and in intraneuronal/intraneuritic aggregates. The hm(2) αSYN transgene resulted in more aggregates and dystrophic neurites than did the hw5 transgene. The hwαSYN transgene resulted in higher expression of two striatal proteins, synaptogamin 7 and UCHL1, compared with the levels of the hm(2) αSYN transgene. These observations suggest that mutations in αSYN may impair specific functional domains, leaving others intact. These lines may be useful for exploring interactions between hαSYN and environmental or genetic risk factors in dopamine-related disorders using a mouse model. 相似文献
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Xuan Q Xu SL Lu DH Yu S Zhou M Uéda K Cui YQ Zhang BY Chan P 《Journal of neural transmission (Vienna, Austria : 1996)》2011,118(11):1575-1583
Although the increased prevalence of Parkinson’s disease (PD) with aging suggests that aging processes predispose dopamine
neurons to degeneration, the mechanism involved remains unknown. Dopamine neurons contain significant amounts of neuromelanin,
and the amount of neuromelanin increases with aging. In the present study, age-related changes in the number of nigral neurons
expressing neuromelanin (NM), α-synuclein, and tyrosine hydroxylase (TH) were stereologically analyzed in the postmortem brains
of 28 healthy humans with an age range of 17–84 years. Stereological counting of NM content, α-synuclein content, and TH immunoreactivity
revealed significant accumulation of NM and α-synuclein in neurons during the aging process. In cells containing a large amount
of NM, α-synuclein-immunoreactive cells in aged individuals outnumbered those of younger individuals. In non-NM cells, the
α-synuclein expression profile was similar across age groups. Furthermore, TH-immunoreactive neurons decreased significantly
with aging, which was associated with accumulation of NM and α-synuclein. Our results suggest that age related accumulation
of NM might induce α-synuclein over-expression and thereby make dopamine neurons more vulnerable to injuries. 相似文献
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Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4 months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease. 相似文献
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Kurt A. Jellinger 《Acta neuropathologica》2009,118(3):371-379
Postencephalitic parkinsonism (PEP), a chronic complication of encephalitis lethargica, is a tauopathy characterized by multisystem
neuronal loss and gliosis with widespread neurofibrillary lesions composed of both 3- and 4-repeat (3R and 4R) tau isoforms.
Previous immunohistochemical studies in a small number of PEP cases demonstrated absence of Lewy bodies as well as the lack
of other α-synuclein pathology, classifying PEP as a “pure” tauopathy. Neuropathologic examination of 10 brains with clinico-pathologically
verified PEP confirmed widespread neurodegeneration in subcortical and brainstem areas associated with multifocal neurofibrillary
pathology comprising both 3R and 4R tau. Very rare β-amyloid deposits were observed in two elderly patients, while Lewy bodies
and neurites or any other α-synuclein deposits were completely absent. The causes and molecular background of total absence
of α-synuclein pathology in PEP, in contrast to most other tauopathies, remain as unknown as the pathogenesis of PEP. 相似文献
7.
Distinctive neuropathology revealed by α-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p 总被引:3,自引:0,他引:3
Gwinn-Hardy K Mehta ND Farrer M Maraganore D Muenter M Yen SH Hardy J Dickson DW 《Acta neuropathologica》2000,99(6):663-672
The identification of the α-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of α-synuclein
as a component of Lewy bodies has heralded a new era in the study of Parkinson’s disease. We have identified a large family
with Lewy body parkinsonism linked to a novel locus on chromosome 4p15 that does not have a mutation in the α-synuclein gene.
Here we report the clinical and neuropathological findings in an individual from this family and describe unusual high molecular
weight α-synuclein-immunoreactive proteins in brain homogenates from brain regions with the most marked neuropathology. Distinctive
histopathology was revealed with α-synuclein immunostaining, including pleomorphic Lewy bodies, synuclein-positive glial inclusions
and widespread, severe neuritic dystrophy. We also discuss the relationship of this familial disorder to a Lewy body disease
clinical spectrum, ranging from Parkinson’s disease to dementia with psychosis.
Received: 15 March 1999 / Revised, accepted: 24 September 1999 相似文献
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Multiple system atrophy is a sporadic, progressive, neurodegenerative disease characterized by an oligodendroglial accumulation of alpha-synuclein (α-syn). The mechanisms underlying the oligodendroglial accumulation of α-syn in the brains of patients with multiple system atrophy have attracted a great deal of interest, given the primarily neuronal role reported for this protein. We examined the interactions between neuronal and oligodendroglial α-syn in the progeny of crosses between parental transgenic (tg) mouse lines that express α-syn either under the oligodendroglial-specific myelin-basic protein promoter (MBP1-hα-syn tg) or under the neuronal platelet-derived growth factor promoter (PDGF-hα-syn tg). Our results demonstrate that progeny from the cross [hα-syn double (dbl) tg mice] displayed a robust redistribution of α-syn accumulation, with a relocalization from a neuronal or a mixed neuronal/oligodendroglial α-syn expression to a more oligodendroglial pattern in both the neocortex and the basal ganglia that closely resembled the parental MBP-hα-syn tg line. The hα-syn dbl tg mice also displayed motor deficits, concomitant with reduced levels of tyrosine hydroxylase and augmented neuropathological alterations in the basal ganglia. These results suggest that the central nervous system milieu in the hα-syn dbl tg mice favors an oligodendroglial accumulation of α-syn. This model represents an important tool to examine the interactions between neuronal and oligodendrocytic α-syn in diseases such as multiple system atrophy. 相似文献
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Mougenot AL Bencsik A Nicot S Vulin J Morignat E Verchère J Bétemps D Lakhdar L Legastelois S Baron TG 《Journal of neuropathology and experimental neurology》2011,70(5):377-385
There is a growing interest in the potential roles of misfolded protein interactions in neurodegeneration. To investigate this issue, we inoculated 3 prion strains intracerebrally into transgenic (TgM83) mice that overexpress human A53T α-synuclein. In comparison to nontransgenic controls, there was a striking decrease in the incubation periods of scrapie, classic and H-type bovine spongiform encephalopathies(C-BSE and H-BSE), with conservation of the histopathologic and biochemical features characterizing these 3 prion strains. TgM83 mice died of scrapie or C-BSE prion diseases before accumulating the insoluble and phosphorylated forms of α-synuclein specific to late stages of synucleinopathy. In contrast, the median incubation time for TgM83 mice inoculated with H-BSE was comparable to that observed when these mice were uninfected, thereby allowing the development of molecular alterations of α-synuclein. The last 4 mice of this cohort exhibited early accumulations of H-BSE prion protein along with α-synuclein pathology. The results indicate that a prion disease was triggered concomitantly with an overt synucleinopathy in some transgenic mice overexpressing human A53T α-synuclein after intracerebral inoculation with an H-BSE prion strain. 相似文献
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Sensitive detection of alpha-synuclein (alpha-syn) pathology is important in the diagnosis of disorders like Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy and in providing better insights into the etiology of these diseases. Several monoclonal antibodies that selectively react with aggregated alpha-syn in pathological inclusions and reveal extensive and underappreciated alpha-syn pathology in the brains of diseased patients were previously reported by Duda et al. (Ann Neurol 52:205-210, 2002). We sought to characterize the specificity of some of these antibodies (Syn 505, Syn 506 and Syn 514); using C-terminal and N-terminal truncations of alpha-syn, all three antibodies were determined to require N-terminal epitopes that minimally comprise amino acids 2-4, but possibly extend to amino acid 12 of alpha-syn. The selectivity of these antibodies was further assessed using biochemical analysis of human brains and reactivity to altered recombinant alpha-syn proteins with duplication variants of amino acids 1-12. In addition, by expressing wild-type or a double mutant (E46K/A53T) of alpha-syn in cultured cells and by comparing their immunoreactivities to another antibody (SNL-4), which has a similar primary epitope, it was determined that Syn 505, Syn 506 and Syn 514 recognize conformational variants of alpha-syn that is enhanced by the presence of the double mutations. These studies indicate that antibodies Syn 505, Syn 506 and Syn 514 preferentially recognize N-terminal epitopes in complex conformations, consistent with the dramatic conformational change associated with the polymerization of alpha-synuclein into amyloid fibrils that form pathological inclusions. 相似文献
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One of the prominent pathological features of Parkinson's disease (PD) is the abnormal accumulation of iron in the substantia nigra pars compacta (SNpc), in the reactive microglia, and in association with neuromelanin, within the melanin-containing dopamine (DA) neurons. Lewy body, the morphological hallmark of PD, is composed of lipids, redox-active iron, and aggregated alpha-synuclein, concentrating in its peripheral halo and ubiquitinated, hyperphosphorylated, neurofilament proteins. The capacity of free iron to enhance and promote the generation of toxic reactive oxygen radicals has been discussed numerous times. Recent observations, that iron induces aggregation of inert alpha-synuclein to toxic aggregates, have reinforced the critical role of iron in oxidative stress-induced pathogenesis of DA neuron degeneration and protein degradation via ubiquitination. N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and 6-hydroxydopamine-induced neurodegeneration in rodents and nonhuman primates is associated with increased presence of iron and alpha-synuclein in the SNpc. The accumulation of iron in MPTP-induced neurodegeneration has been linked to nitric oxide-dependent mechanism, resulting in degradation of prominent iron regulatory proteins by ubiquitination. Radical scavengers such as R-apomorphine and green tea catechin polyphenol (-)-epigallocatechin-3-gallate, as well as the recently developed brain-permeable VK-28 series derivative iron chelators, which are neuroprotective against these neurotoxins in mice and rats, prevent the accumulation of iron and alpha-synuclein in SNpc. This study supports the notion that a combination of iron chelation and antioxidant therapy, as emphasized on several occasions, might be a significant approach to neuroprotection in PD and other neurodegenerative diseases. 相似文献
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Yin J Han J Zhang C Ma QL Li X Cheng F Liu G Li Y Uéda K Chan P Yu S 《Journal of neural transmission (Vienna, Austria : 1996)》2011,118(8):1155-1164
Although abnormal aggregation of ??-synuclein (??-syn) is involved in several neurodegenerative diseases, its biological functions remain poorly understood, which limits our understanding of its pathogenic mechanisms. ??-Syn exhibits MAP-like activity and promotes the assembly of microtubules. Since microtubules play a pivotal role in proliferative cell division, it is possible that ??-syn affects cell proliferation by facilitating microtubule assembly. The role of ??-syn in promoting cell proliferation was reported previously in PC12 dopaminergic cells overexpressing ??-syn. Here, we extended this study aiming at finding the association between the cell proliferation effect of ??-syn and its microtubule assembly activity, and identifying the potential active domain for the effect of ??-syn on cell proliferation. By exploiting the property that the 11-mer repeats of synuclein molecules are able to mediate a rapid intracellular translocation of these proteins across the plasma membrane without being degraded by the cellular proteolytic system, we added recombinant full-length ??-syn (wild type and A53T and A30P mutants) and ??-syn to the culture medium of MES23.5 dopaminergic cells, and observed their intracellular translocation, subcellular distribution and effects on cell proliferation. We found that all the synuclein molecules could enter the cells where they were localized in both the cytoplasm and nucleus. However, only the wild-type ??-syn, which had been shown to have microtubule assembly activity, was able to promote proliferation of the MES23.5 cells. The A53T and A30P mutant ??-syn as well as ??-syn, which had been proved not to possess microtubule assembly activity, did not exhibit any effect on cell proliferation. Since the ??-syn activity in microtubule assembly was shown to be related to its specific functional domain, we then generated different functional fragments (N-terminal aa1?C65, NAC aa61?C95 and C-terminal aa96?C140) and tested their activities in cell proliferation. We showed that all the ??-syn fragments could enter the cells, but with different subcellular localizations. The N-terminal and NAC fragments were localized in the cytoplasm and the C-terminal fragment mainly in the nucleus. In accordance with the activity for the C-terminal part of ??-syn in microtubule assembly, only the NAC and C-terminal fragments exhibited the activity in cell proliferation. The N-terminal fragment without microtubule assembly activity did not promote cell proliferation. The above results suggest that the ??-syn function in promoting cell proliferation is associated with its microtubule assembly activity with the functional domain localized in its C-terminal part. 相似文献
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Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disease affecting the indigenous Chamorro population of Guam. Neuropathologically, PDC is characterized by neuronal loss in the substantia nigra pars compacta with severe widespread neurofibrillary tangles (NFTs) similar to those observed in Alzheimers disease (AD), and is thus considered a tauopathy. Following reports of -synuclein pathology in PDC patients of Guam, PDC has also been neuropathologically classified as a synucleinopathy. Recently, the presence of -synuclein-positive bodies has been reported in the cerebellum of some patients with Parkinsons disease (PD), diffuse Lewy body disease (DLBD), or multiple system atrophy (MSA). Using immunohistochemical techniques, we investigated the deposition of -synuclein in the cerebellum of Guamanian PDC patients. Numerous -synuclein-immunoreactive spherical structures were found in the molecular layer of the cerebellum of 63.6% of PDC patients. These structures were only seen in patients showing -synuclein pathology in the amygdala. The average density of -synuclein-immunoreactive structures in the cerebellum of Guamanian PDC patients was almost an order of magnitude higher than in non-Guamanian PD patients, and this -synuclein pathology was much more pronounced in the hemisphere than in the vermis. In addition, double immunohistochemistry revealed that cerebellar -synuclein is co-localized with the neuronal marker calbindin and with glial-fibrillary acidic protein, suggesting the involvement of Purkinje cells and Bergmann glia. These findings demonstrate that the -synuclein pathology in PDC of Guam affects not only the amygdala, but also the cerebellum, where it appears to involve both Purkinje cells and specialized astrocytes. 相似文献
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David Hilton Madeleine Stephens Leanne Kirk Philip Edwards Ross Potter John Zajicek Ellie Broughton Hannah Hagan Camille Carroll 《Acta neuropathologica》2014,127(2):235-241
Parkinson’s disease primarily affects the central nervous system, but autopsy and small patient studies have revealed autonomic nervous system pathology in most cases. We looked for α-synuclein pathology in routinely acquired biopsies from patients and matched controls. Immunocytochemistry was performed and assessed blind to the clinical diagnoses. One hundred and seventeen gastrointestinal tissue samples from 62 patients, and 161 samples from 161 controls, were examined. Twelve biopsies from seven patients showed accumulation of α-synuclein within mucosal and submucosal nerve fibres, and ganglia, which was more extensive with an antibody to phosphorylated, than with an antibody to non-phosphorylated, α-synuclein. These included gastric, duodenal and colonic biopsies, and were taken up to 8 years prior to the onset of motor symptoms. All patients with positive biopsies had early autonomic symptoms and all controls were negative. This large scale study demonstrates that accumulation of α-synuclein in the gastrointestinal tract is a highly specific finding that could be used to confirm a clinical diagnosis of Parkinson’s disease. We have shown that α-synuclein accumulation occurs prior to the onset of motor symptoms in the upper, as well as the lower gastrointestinal tract, remains present in serial biopsies until the onset of motor symptoms and is predominantly composed of phosphorylated α-synuclein. Accumulation of α-synuclein in the bowel therefore offers an accessible biomarker which allows further study of the early stages of the disease and could be of value in the assessment of disease modifying treatments. 相似文献
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X Lin L Parisiadou C Sgobio G Liu J Yu L Sun H Shim XL Gu J Luo CX Long J Ding Y Mateo PH Sullivan LG Wu DS Goldstein D Lovinger H Cai 《The Journal of neuroscience》2012,32(27):9248-9264
α-Synuclein (α-syn) plays a prominent role in the degeneration of midbrain dopaminergic (mDA) neurons in Parkinson's disease (PD). However, only a few studies on α-syn have been performed in the mDA neurons in vivo, which may be attributed to a lack of α-syn transgenic mice that develop PD-like severe degeneration of mDA neurons. To gain mechanistic insights into the α-syn-induced mDA neurodegeneration, we generated a new line of tetracycline-regulated inducible transgenic mice that overexpressed the PD-related α-syn A53T missense mutation in the mDA neurons. Here we show that the mutant mice developed profound motor disabilities and robust mDA neurodegeneration, resembling some key motor and pathological phenotypes of PD. We also systematically examined the subcellular abnormalities that appeared in the mDA neurons of mutant mice and observed a profound decrease of dopamine release, the fragmentation of Golgi apparatus, and the impairments of autophagy/lysosome degradation pathways in these neurons. To further understand the specific molecular events leading to the α-syn-dependent degeneration of mDA neurons, we found that overexpression of α-syn promoted a proteasome-dependent degradation of nuclear receptor-related 1 protein (Nurr1), whereas inhibition of Nurr1 degradation ameliorated the α-syn-induced loss of mDA neurons. Given that Nurr1 plays an essential role in maintaining the normal function and survival of mDA neurons, our studies suggest that the α-syn-mediated suppression of Nurr1 protein expression may contribute to the preferential vulnerability of mDA neurons in the pathogenesis of PD. 相似文献
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Hashimoto M Kawahara K Bar-On P Rockenstein E Crews L Masliah E 《Journal of molecular neuroscience : MN》2004,24(3):343-352
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are members of a family of disorders characterized by the presence
of inclusion bodies, or Lewy bodies (LBs), filled with aggregates of α-synuclein. These diseases are a leading cause of movement
disorders and dementia in the aging population, and it is crucial to understand the factors leading to the accumulation and
assembly of these α-synuclein aggregates. Previous studies have uncovered much about the factors leading to aggregation and
the mechanisms causing neurotoxicity of these inclusion bodies; however, little is known about factors that promote the degradation
and prevent the aggregation of α-synuclein. The present article provides a review of recent efforts in the investigation of
factors involved in α-synuclein metabolism and the mechanisms involved in preventing accumulation of α-synuclein and degrading
this molecule. Understanding these processes might provide targets for the development of novel therapies for disorders such
as DLB and PD. 相似文献
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Cullen V Sardi SP Ng J Xu YH Sun Y Tomlinson JJ Kolodziej P Kahn I Saftig P Woulfe J Rochet JC Glicksman MA Cheng SH Grabowski GA Shihabuddin LS Schlossmacher MG 《Annals of neurology》2011,69(6):940-953