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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease. The function of alpha-synuclein has not been deciphered yet; however, it might play a role in vesicle function, transport, or as a chaperone. alpha-Synuclein belongs to a family of three proteins, which includes beta- and gamma-synuclein. gamma-Synuclein shares 60% similarity with alpha-synuclein. Similar to alpha-synuclein, a physiological function for gamma-synuclein has not been defined yet, but it has been implicated in tumorgenesis and neurodegeneration. Interestingly, neither alpha- (SNCA(-/-)), gamma- (SNCG(-/-)), nor alpha/gamma- (SNCA_G(-/-)) deficient mice are present with any obvious phenotype. Using microarray analysis, we thus investigated whether deficiency of alpha- and gamma-synuclein leads to similar compensatory mechanisms at the RNA level and whether similar transcriptional signatures are altered in the brain. Sixty-five genes were differentially expressed in all mice. SNCA(-/-) mice and SNCG(-/-) mice shared 84 differentially expressed genes, SNCA(-/-) and SNCA_G(-/-) expressed 79 genes, and SNCG(-/-) and SNCA_G(-/-) expressed 148 genes. For many of the physiological pathways such as dopamine receptor signaling (down-regulated), cellular development, nervous system function, and cell death (up-regulated), we found groups of genes that were similarly altered in SNCA(-/-) and SNCG(-/-) mice. In one of the pathways altered in both models, we found Mapk1 as the core transcript. Other gene groups, however, such as TGF-beta signaling and apoptosis pathways genes were significantly up-regulated in the SNCA(-/-) mice but down-regulated in SNCG(-/-) mice. beta-synuclein expression was not significantly altered in any of the models.
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PMID:Whole genome expression analyses of single- and double-knock-out mice implicate partially overlapping functions of alpha- and gamma-synuclein. 1731 38

Neurodegeneration in Parkinson's disease (PD) is accompanied by a local immune reaction in the affected brain regions. It is well established that alpha-synuclein is directly implicated in the pathogenesis of PD. Development of the disease is often associated with changes of expression and cellular compartmentalisation of this protein; moreover, its oligomers or protofibrils are often released to the CSF and plasma of patients. Aggregated alpha-synuclein can trigger the activation of microglia; however, its capacity to induce production of specific autoantibodies (AAb) has not been assessed. In this study, we examined the presence of AAb against synuclein family members in the peripheral blood serum of PD patients and control individuals. Presence of AAb against beta-synuclein or gamma-synuclein showed no association with PD. Multi-epitopic AAb against alpha-synuclein were detected in 65% of all patients tested and their presence strongly correlated with an inherited mode of the disease but not with other disease-related factors. The frequency of the presence of AAb in the studied group of patients with sporadic form of PD was not significantly different from the frequency in the control group but very high proportion (90%) of patients with familial form of the disease were positive for AAb against alpha-synuclein. We hypothesise that these AAb could be involved in pathogenesis of the inherited form of PD.
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PMID:Autoantibodies to alpha-synuclein in inherited Parkinson's disease. 1744 46

The human synuclein protein family includes alpha-synuclein, which has been linked to both familial and sporadic Parkinson's disease, and the highly homologous beta and gamma-synuclein. Mutations in alpha-synuclein cause autosomal dominant early onset Parkinson's, and the protein is found deposited in a fibrillar form in hereditary and idiopathic forms of the disease. No genetic link between beta and gamma-synuclein, and any neurodegenerative disease has been established, and it is generally considered that these proteins are not highly pathogenic. In addition, beta and gamma-synuclein are reported to aggregate less readily than alpha-synuclein in vitro. Indeed, beta-synuclein has been reported to protect against alpha-synuclein aggregation in vitro, as well as alpha-synuclein-mediated toxicity in vivo. Earlier, we compared the structural properties of the highly helical states adopted by all three synucleins in association with detergent micelles in an attempt to delineate the basis for functional differences between the three proteins. Here, we report a comparison of the structural and dynamic properties of the free states of all three proteins in order to shed light on differences that may help to explain their different propensities to aggregate, which in turn may underlie their differing contributions to the etiology of Parkinson's disease. We find that gamma-synuclein closely resembles alpha-synuclein in its free-state residual secondary structure, consistent with the more similar propensities of the two proteins to aggregate in vitro. beta-Synuclein, however, differs significantly from alpha-synuclein, exhibiting a lower predisposition towards helical structure in the second half of its lipid-binding domain, and a higher preference for extended structures in its C-terminal tail. Both beta and gamma-synuclein show less extensive transient long-range structure than that observed in alpha-synuclein. These results raise questions regarding the role of secondary structure propensities and transient long-range contacts in directing synuclein aggregation reactions.
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PMID:Residual structure, backbone dynamics, and interactions within the synuclein family. 1768 34

The synuclein family of intrinsically unfolded proteins is composed of three highly homologous members, alpha-synuclein (alphaS), beta-synuclein (betaS) and gamma-synuclein (gammaS), which are linked to neurodegenerative disorders and cancer. alphaS has been studied intensively after its identification as the major protein component of amyloid-like deposits in Parkinson's disease and dementia with Lewy bodies. betaS, on the other hand, was found to act as a potent inhibitor of alphaS amyloid formation, and it is proposed as a natural regulator of its neurotoxicity. It is then of particular interest to elucidate the structural and dynamic features of the soluble state of betaS as a first step to understand the molecular basis of its anti-amyloidogenic effect on alphaS. We present here the characterization of natively unstructured betaS by high resolution heteronuclear NMR techniques. A combination of pulse-field gradient, three-dimensional heteronuclear correlation, residual dipolar couplings, paramagnetic relaxation enhancement and backbone relaxation experiments were employed to characterize the ensemble of conformations populated by the protein. The results indicate that betaS adopts extended conformations in its native state, characterized by the lack of the long-range contacts as previously reported for alphaS. Despite the lack of defined secondary structure, we found evidence for transient polyproline II conformations clustered at the C-terminal region. The structuring of the backbone at the C terminus is locally encoded, stabilized by the presence of eight proline residues embedded in a polypeptide stretch rich in hydrophilic and negatively charged amino acids. The structural and functional implications of these findings are analyzed via a thorough comparison with its neurotoxic homolog alphaS.
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PMID:Structural characterization of the intrinsically unfolded protein beta-synuclein, a natural negative regulator of alpha-synuclein aggregation. 1768 39

Alpha-synuclein is intimately involved in the pathogenesis of Parkinson's disease, and has been implicated in the regulation of synthesis, release and reuptake of dopamine (DA). However, mice lacking members of the synuclein family have been reported to display no overt behavioural phenotype. This may be a result of compensatory upregulation of other synucleins during development. Here we report on behaviour and DA synapse function of alpha-synuclein null, gamma-synuclein null, and alpha-gamma-synuclein double-null knockout mice. Double-null mice were hyperactive in a novel environment and alternated at a lower rate in a T-maze spontaneous alternation task, a phenotype reminiscent of mice expressing reduced levels of the DA transporter. To investigate a possible hyperdopaminergic phenotype in alpha-gamma-synuclein double-null mice, we used fast-scan cyclic voltammetry at carbon-fibre microelectrodes to assess DA release and reuptake in striatal slices from wild-type, alpha-null, gamma-null and double-null mice in real time. Double-null mice were found to have a twofold increase in the extracellular concentration of DA detected after discrete electrical stimuli in the striatum. By measuring the rate of reuptake of DA and tissue DA content in these animals, we showed that the observed increase in size of striatal DA transients was not attributable to a decrease in reuptake of DA via the DA transporter, and can not be attributed to an increase in tissue DA levels in the striatum. Rather, we propose that loss of both alpha- and gamma-synuclein causes an increase in release probability from dopaminergic synapses.
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PMID:Increased striatal dopamine release and hyperdopaminergic-like behaviour in mice lacking both alpha-synuclein and gamma-synuclein. 1833 65

The gamma-synuclein protein is involved in breast carcinogenesis and has also been implicated in other forms of cancer and in ocular diseases. Furthermore, gamma-synuclein is believed to have a role in certain neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. This work reports the cloning and characterization of the porcine (Sus scrofa) gamma-synuclein cDNA (SNCG). The SNCG cDNA was amplified by reverse transcriptase polymerase chain reaction (RT-PCR) using oligonucleotide primers derived from in silico sequences. The porcine SNCG cDNA codes for a protein of 126 amino acids which shows a high similarity to bovine (90%), human (87%) and mouse (83%) gamma-synuclein. A genomic clone containing the entire porcine SNCG gene was isolated and its genomic organization determined. The gene is composed of five exons, the general structure being observed to be very similar to that of the human SNCG gene. Expression analysis by quantitative real-time RT-PCR revealed the presence of SNCG transcripts in all examined organs and tissues. Differential expression was observed, with very high levels of SNCG mRNA in fat tissue and high expression levels in spleen, cerebellum, frontal cortex and pituitary gland. Expression analysis also showed that porcine SNCG transcripts could be detected in different brain regions during early stages of embryo development. The porcine SNCG orthologue was mapped to chromosome 14q25-q29. The distribution of recombinant porcine gamma-synuclein was studied in three different transfected cell lines and the protein was found to be predominantly localized in the cytoplasm.
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PMID:Porcine gamma-synuclein: molecular cloning, expression analysis, chromosomal localization and functional expression. 1846 69

The neuronal protein alpha-synuclein has been linked to the pathogenesis of synucleinopathies, a collection of neurodegenerative disorders, including Parkinson's disease. alpha-Synuclein belongs to a family of synuclein genes that includes beta- and gamma-synuclein. However, despite being associated with several fatal human neurodegenerative diseases, little is known about the normal function of synucleins. Here we report the cloning and characterization of three synucleins from zebrafish, sncga, sncgb, and sncb. The sequences of these zebrafish synucleins are very similar to those of the human proteins. We used whole-mount in situ hybridization to analyze their spatial and temporal expression patterns during development. sncgb was expressed exclusively in the notochord, while sncga and sncb were expressed strongly in the nervous system. Our identification of synuclein genes in zebrafish and the characterization of their expression patterns will facilitate future experiments aimed at assessing their functions in normal physiology as well as their role in pathophysiology.
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PMID:Discovery and characterization of three novel synuclein genes in zebrafish. 1852 55

Synucleins are widely expressed synaptic proteins within the central nervous system that have been implicated in such neurodegenerative disorders as Parkinson's disease. In this study, an initial characterization of all three synucleins, alpha-, beta-, and gamma-synuclein, within the cochlea was undertaken. Reverse transcriptase-polymerase chain reaction (PCR) demonstrated all three synuclein mRNA species within microdissected cochlear tissue. Quantitative PCR suggests that beta-synuclein is the most abundantly expressed form, followed by gamma- and then alpha-synuclein. Western blot analysis similarly demonstrates all three synuclein proteins within microdissected cochlear tissue. Immunofluorescence localizes the three synucleins predominantly to the efferent neuronal system at the efferent outer hair cell synapse, with some additional localization within the efferent tunnel-crossing fibers (alpha- and gamma-synuclein), spiral ganglion (beta-synuclein), inner spiral bundle (gamma-synuclein), and stria vascularis (alpha- > beta-synuclein). Developmentally, gamma-synuclein can be seen in the region of the outer hair cells by E19, while alpha- and beta-synuclein do not clearly appear there until approximately P10. Additional studies in a null-mutant gamma-synuclein mouse show no histological changes in the organ of Corti with normal hair cell and spiral ganglion cell counts, and normal ABR and DPOAE thresholds in wild-type vs mutant littermates. Together, these results localize synucleins to the efferent cholinergic neuronal auditory system, pointing to a role in normal auditory function, and raising the potential implications for their role in auditory neurodegenerative disorders. However, gamma-synuclein alone is not required for the development and maintenance of normal hearing through P21. Whether overlapping roles of the other synucleins help compensate for the loss of gamma-synuclein remains to be determined.
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PMID:Localization of synucleins in the mammalian cochlea. 1866 22

Synucleins are small, soluble proteins expressed primarily in neural tissues and certain tumors. The family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein. A typical structural feature of synucleins is the presence of a repetitive, degenerative AA motif KTKEGV throughout the first 87 residues and acidic stretches within the C-terminal region. Members of the synuclein family are natively unfolded proteins that are characterized by a high net charge and low hydropathy. The synuclein family recently came into the spotlight when one of its members, alpha-synuclein, was linked both genetically and neuropathologically to Parkinson's disease. It has a role in other neurodegenerative diseases, such as dementia with Lewy bodies, multiple system atrophy, neurodegeneration with brain iron accumulation type 1, and Alzheimer's disease. Interestingly, another member of the family, beta-synuclein, possesses antagonistic properties to alpha-synuclein. The third member of the family, gamma-synuclein, is implicated in different types of cancer, some neurodegenerative diseases and ocular pathology. The involvement of synuclein proteins in the etiology of common human diseases has raised exciting questions and is currently the subject of intense investigation.
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PMID:Molecular and cellular biology of synucleins. 1908 38

The role of alpha-synuclein in pathogenesis of familial and idiopathic forms of Parkinson's disease, and other human disorders known as alpha-synucleinopathies, is well established. In contrast, the involvement of two other members of the synuclein family, beta-synuclein and gamma-synuclein, in the development and progression of neurodegeneration is poorly studied. However, there is a growing body of evidence that alpha-synuclein and beta-synuclein have opposite neuropathophysiological effects. Unlike alpha-synuclein, overexpressed beta-synuclein does not cause pathological changes in the nervous system of transgenic mice and even ameliorates the pathology caused by overexpressed alpha-synuclein. To assess the consequences of excess expression of the third family member, gamma-synuclein, on the nervous system we generated transgenic mice expressing high levels of mouse gamma-synuclein under control of Thy-1 promoter. These animals develop severe age- and transgene dose-dependent neuropathology, motor deficits and die prematurely. Histopathological changes include aggregation of gamma-synuclein, accumulation of various inclusions in neuronal cell bodies and processes, and astrogliosis. These changes are seen throughout the nervous system but are most prominent in the spinal cord where they lead to loss of spinal motor neurons. Our data suggest that down-regulation of small heat shock protein HSPB1 and disintegration of neurofilament network play a role in motor neurons dysfunction and death. These findings demonstrate that gamma-synuclein can be involved in neuropathophysiological changes and the death of susceptible neurons suggesting the necessity of further investigations of the potential role of this synuclein in disease.
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PMID:Gamma-synucleinopathy: neurodegeneration associated with overexpression of the mouse protein. 1924 16


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