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1.
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Some of the inherited forms of the disease are caused by mutations in the alpha-synuclein gene and the triplication of its locus. Oxidative stress has been proposed as a central mechanism for the progression of the disease although its relation with alpha-synuclein toxicity remains obscure. Targeted expression of human alpha-synuclein has been effectively used to recreate the pathology of PD in Drosophila melanogaster and it has been proved an excellent tool for the study of testable hypothesis in relation to the disease. We show that dopaminergic neurons are specifically sensitive to hyperoxia induced oxidative stress and that mutant forms of alpha-synuclein show an enhanced toxicity under these conditions suggesting synergic interactions. In addition, the co-expression of Cu/Zn superoxid dismutase protects against the dopaminergic neuronal loss induced by mutant alpha-synuclein overexpression thus identifying oxidative stress as an important causative factor in the pathology of autosomal-dominant Parkinsonism.  相似文献   

2.
Neuropathology in mice expressing human alpha-synuclein.   总被引:32,自引:0,他引:32  
The presynaptic protein alpha-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. alpha-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the alpha-synuclein gene are genetically linked to rare familial forms of Parkinson's disease. Under control of mouse Thy1 regulatory sequences, expression of A53T mutant human alpha-synuclein in the nervous system of transgenic mice generated animals with neuronal alpha-synucleinopathy, features strikingly similar to those observed in human brains with Lewy pathology, neuronal degeneration, and motor defects, despite a lack of transgene expression in dopaminergic neurons of the substantia nigra pars compacta. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions in several muscles examined, suggesting that alpha-synuclein interfered with a universal mechanism of synapse maintenance. Thy1 transgene expression of wild-type human alpha-synuclein resulted in similar pathological changes, thus supporting a central role for mutant and wild-type alpha-synuclein in familial and idiotypic forms of diseases with neuronal alpha-synucleinopathy and Lewy pathology. These mouse models provide a means to address fundamental aspects of alpha-synucleinopathy and test therapeutic strategies.  相似文献   

3.
Mutations in the human alpha-synuclein gene have been identified in several families of European descent with early-onset Parkinson's disease (PD). We sequenced the complete alpha-synuclein cDNA from substantia nigra and cortex from nine patients with PD and eight control subjects. No mutations were found. We then analyzed alpha-synuclein mRNA levels using a ribonuclease protection assay. Two major protected bands of alpha-synuclein mRNA, possibly representing two splice variants of the gene, were observed. Alpha-synuclein mRNA was significantly diminished in the substantia nigra of patients with PD compared with control subjects but not in the cortex. Our findings suggest that decreased synuclein mRNA may be an early alteration in the SN in PD, and imply that decreased levels of the protein may play a role in the pathogenesis of sporadic cases of the disease.  相似文献   

4.
Lewy bodies, the pathological hallmark of Parkinson's disease (PD), consist largely of alpha-synuclein, a 14.5-kDa presynaptic neuronal protein implicated in familial PD. An increased copy number and elevated expression of wild-type alpha-synuclein (SNCA) has been shown to cause early-onset familial PD. However, it is not clear whether increased alpha-synuclein expression also plays a role in the pathogenesis of sporadic disease. In the current study, we analyzed the levels of SNCA-mRNA in affected brains of sporadic PD patients. We compared the levels of steady state SNCA-mRNA in 7 sporadic PD brain samples and 7 normal controls using real-time polymerase chain reaction of RNA extracted from mid-brain tissue, including the substantia nigra. Despite that there is neuronal loss in the substantia nigra of PD brains, overall the SNCA-mRNA levels were increased in PD brains an average of nearly fourfold over normal control mid-brain, although there was much greater variability in samples from PD patients compared to controls. Frontal cortex samples from selected individuals were also analyzed. SNCA-mRNA levels were not significantly changed in PD frontal cortex compared to controls. These results suggest that elevated expression levels of SNCA-mRNA are found in the affected regions of PD brain and support the hypothesis that increases in alpha-synuclein expression is associated, among other factors, with the development of sporadic PD.  相似文献   

5.
Parkinson disease (PD) targets dopaminergic neurons in the substantia nigra, resulting in motor disturbances such as resting tremor, bradykinesia, and rigidity. Pathogenic processes likely occur over several decades, in that an overwhelming percentage of neurons are already dead at the time of clinical diagnosis. For this reason, the usage of animal model systems to discover the early steps in the pathologic cascade is required. These include exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which selectively kills dopamine neurons in the substantia nigra, and genetic models incorporating mutations in the alpha-synuclein gene that cause disease in human patients. Through the evaluation of these models at multiple time points, it is possible to discover novel gene expression changes that may underlie disease pathogenesis. Specifically, the authors hypothesize that animal models of PD and human PD brains share a gene expression profile that signifies certain aspects of pathogenesis and/or recovery-resistance. To test this and similar hypotheses, the authors and others have utilized new microarray technology that enables the sampling of thousands of genes' expression level in one assay. Because the technology is fairly new and results can vary depending on methods used, results must be evaluated with care. Multiple array and data-mining options can be used to make the most accurate inferences as to differentially expressed genes in each set of samples. The authors developed a fusion classifier approach whereby individual data-mining algorithms generate lists of significant genes. The lists are subsequently queried, and only genes unanimously called significant are retained for further validation. Although the authors' approach identified hundreds of differentially expressed genes in each of three PD systems, only a few were common between the human and animal substantia nigra. These were related to dopamine phenotype, synaptic function, and the mitochondrial metabolism, implicating the presynaptic terminal as a primary site of injury. The time course of the authors' experiments indicates that if the synaptic changes could be prevented, this may alleviate some cell death, in that these changes precede neuronal loss.  相似文献   

6.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the appearance of intracytoplasmic inclusions called Lewy bodies (LB) in dopamine neurons in the substantia nigra and the progressive loss of these neurons. Recently, mutations in the alpha-synuclein gene have been identified in early-onset familial PD, and alpha-synuclein has been shown to be a major component of LB in all patients. Yet, the pathophysiological function of alpha-synuclein remains unknown. In this report, we have investigated the toxic effects of adenovirus-mediated alpha-synuclein overexpression on dopamine neurons in rat primary mesencephalic cultures and in a rat dopaminergic cell line - the large T-antigen immortalized, mesencephalon-derived 1RB3AN27 (N27). Adenovirus-transduced cultures showed high-level expression of alpha-synuclein within the cells. Overexpression of human mutant alpha-synuclein (Ala(53)Thr) selectively induced apoptotic programmed cell death of primary dopamine neurons as well as N27 cells. The mutant protein also potentiated the neurotoxicity of 6-hydroxydopamine (6-OHDA). By contrast, overexpression of wild-type human alpha-synuclein was not directly neurotoxic but did increase cell death after 6-OHDA. Overexpression of wild-type rat alpha-synuclein had no effect on dopamine cell survival or 6-OHDA neurotoxicity. These results indicate that overexpression of human mutant alpha-synuclein directly leads to dopamine neuron death, and overexpression of either human mutant or human wild-type alpha-synuclein renders dopamine neurons more vulnerable to neurotoxic insults.  相似文献   

7.
The presynaptic protein alpha-synuclein is considered to play an important role in the pathophysiology of Parkinson's disease (PD). Point mutations in the alpha-synuclein gene have been demonstrated in familial PD and alpha-synuclein is a major component of Lewy bodies, the pathological hallmark of the sporadic disease. It is not clear whether abnormal accumulation of alpha-synuclein is the result of abnormal levels of expression of the gene in neurodegenerative conditions. Expression of alpha-synuclein mRNA was therefore studied in control and PD brain using semiquantitative in situ hybridization. alpha-synuclein was expressed widely and hybridization signal was seen in most cortical regions, hippocampus, cerebellum, and brain stem. There was little mRNA in the striatum and no hybridization signal was detected in glia. High levels of alpha-synuclein mRNA expression in neurons did not seem to be a marker for Lewy body formation. Abundant signal was seen both in regions in which Lewy body deposition occurs commonly in idiopathic PD (PD), such as substantia nigra and frontal and temporal cortex, as well as in less susceptible regions, e.g. visual cortex. Quantitative comparison of mRNA expression in regions of predilection for Lewy body formation showed that mRNA expression was reduced significantly in melanized substantia nigra neurons and frontal cortex neurons in Parkinson's disease. In substantia nigra neurons there seemed to be a negative correlation between cellular mRNA expression and disease duration. These findings are in broad agreement with other studies of the expression of alpha-synuclein mRNA in human brain and suggest that Lewy body formation is unlikely to be the result of overexpression of alpha-synuclein.  相似文献   

8.
alpha-Synuclein has been identified as a major component of Lewy body inclusions, which are one of the pathologic hallmarks of idiopathic Parkinson's disease. Mutations in alpha-synuclein have been found to be responsible for rare familial cases of Parkinsonism. To test whether overexpression of human alpha-synuclein leads to inclusion formation and neuronal loss of dopaminergic cells in the substantia nigra, we made transgenic mice in which the expression of wild-type or mutant (A30P and A53T) human alpha-synuclein protein was driven by the promoter from the tyrosine hydroxylase gene. Even though high levels of human alpha-synuclein accumulated in dopaminergic cell bodies, Lewy-type-positive inclusions did not develop in the nigrostriatal system. In addition, the number of nigral neurons and the levels of striatal dopamine were unchanged relative to non-transgenic littermates, in mice up to one year of age. These findings suggest that overexpression of alpha-synuclein within nigrostriatal dopaminergic neurons is not in itself sufficient to cause aggregation into Lewy body-like inclusions, nor does it trigger overt neurodegenerative changes.  相似文献   

9.
Mutations in the alpha-synuclein gene have been linked to rare cases of familial Parkinson's disease (PD). Alpha-synuclein is a major component of Lewy bodies (LB), a pathological hallmark of PD. Transgenic mice and Drosophila expressing either wild-type or mutant human alpha-synuclein develop motor deficits, LB-like inclusions in some neurons, and neuronal degeneration. However, the relationship between abnormal aggregates of alpha-synuclein and human dopamine (DA) neuron degeneration remains unclear. In this report, we have investigated the influence of alpha-synuclein expression on DA neurons in primary culture of embryonic human mesencephalon. Two days after culture, human DA cells were transduced with wild-type or mutant human (Ala(53)Thr) alpha-synuclein adenoviruses and maintained for 5 days. Overexpression of mutant and wild-type human alpha-synuclein resulted in 49% (P<0.01) and 27% (P<0.05) loss of DA neurons, respectively, while not affecting viability of other cells in the culture. Overexpression of rat alpha-synuclein or GFP (green fluorescent protein) had no effect on DA neuron survival. Cytoplasmic inclusions of alpha-synuclein were detected immunohistochemically in DA cells transduced with mutant human alpha-synuclein, but not wild-type alpha-synuclein. These results show that overexpression of human alpha-synuclein, particularly the mutant form, can cause human DA neuron death, suggesting that alpha-synuclein may have a primary role in the pathogenesis of PD.  相似文献   

10.
Neuronal pentraxin II (NPTX2) is the most highly upregulated gene in the Parkinsonian substantia nigra based on our whole genome expression profiling results. We show here that it is a novel component of Lewy bodies and Lewy neurites in sporadic Parkinson’s disease (PD). NPTX2 is also known as the neuronal activity-regulated protein (Narp), which is secreted and involved in long-term neuronal plasticity. Narp further regulates AMPA receptors which have been found to mediate highly selective non-apoptotic cell death of dopaminergic neurons. NPTX2/Narp is found in close association with alpha-synuclein aggregates in both substantia nigra and cerebral cortex in PD but unlike alpha-synuclein gene expression, which is down-regulated in the Parkinsonian nigra, NPTX2 could represent a driver of the disease process. In view of its profound (>800%) upregulation and its established role in synaptic plasticity as well as dopaminergic nerve cell death, NPTX2 is a very interesting novel player which is likely to be involved in the pathway dysregulation which underlies PD. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. This work was supported by the Parkinson’s Disease Society of the UK.  相似文献   

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