Gene/Protein Disease Symptom Drug Enzyme Compound
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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 is believed to play an important role in Parkinson's disease (PD). Mutations in the alpha-synuclein gene are responsible for familial forms of PD and alpha-synuclein protein is a major component of Lewy bodies in patients with sporadic PD. Synphilin-1 is a novel protein that we have previously found to associate in vivo with alpha-synuclein. We now show that synphilin-1 is present in Lewy bodies of patients with PD. Our data suggest that synphilin-1 could play a role in Lewy body formation and the pathogenesis of PD.
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PMID:Synphilin-1 is present in Lewy bodies in Parkinson's disease. 1076 66

alpha-Synuclein is present in Lewy bodies of patients with both sporadic and familial Parkinson's disease. However, pathogenic mutations Ala30Pro and Ala53Thr in alpha-synuclein are rare causes of disease. Synphilin-1 has been demonstrated to associate with alpha-synuclein and promote the formation of cytosolic inclusions in vitro. Two-point genetic linkage analysis of a dinucleotide repeat within the synphilin-1 gene initially implicated this locus as a cause of Parkinson's disease in three of nine families. However, subsequent haplotype, sequencing, and association analyses in these three families and an independent case-control series suggest that variability within the locus does not confer susceptibility to Parkinson's disease.
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PMID:Genetic analysis of synphilin-1 in familial Parkinson's disease. 1130 Jul 26

alpha-Synuclein is mutated in rare autosomal dominant forms of Parkinson's disease and is a major component of Lewy bodies and neurites. Synphilin-1, a novel protein interacts in vivo and co-localises with alpha-synuclein in Lewy bodies. We analysed the synphilin-1 gene in familial Parkinson's disease by single-strand conformation polymorphism (SSCP) and automated sequencing but found no coding mutations. However, we identified two novel intronic polymorphisms; an A/T polymorphism in intron 2, resulting in the introduction of an Alu1 site and a second G/T polymorphism in intron 4. We analysed the intron 2 polymorphism for allelic association as it was conducive to rapid screening but observed no changes in frequency between Parkinson's disease cases and controls.
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PMID:No pathogenic mutations in the synphilin-1 gene in Parkinson's disease. 1142 16

The discovery of mutations in the gene for alpha-synuclein in familial Parkinson's disease (PD) has led to an increased interest in this pre-synaptic protein. Synphilin-1, a potential synuclein-binding protein, was cloned using yeast two-hybrid assays. The function of synphilin-1 is currently unknown, although it has been reported to be present along with alpha-synuclein in Lewy bodies in PD. In the present study, we monitored synphilin-1 aggregation directly using fusion proteins of synphilin-1 and green fluorescent protein (EGFP). Transfection of synphilin-EGFP fusion proteins formed cytoplasmic inclusions in HEK293 cells. Although these inclusions overlapped with the distribution of alpha-synuclein, they were unlike Lewy bodies in that they were not eosinophilic, and instead were membrane-bound, lipid-rich cytoplasmic inclusions.
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PMID:Transfected synphilin-1 forms cytoplasmic inclusions in HEK293 cells. 1174 67

Alpha-synuclein is the major component of Lewy bodies in patients with Parkinson's disease, and mutations in the alpha-synuclein gene are responsible for some familial forms of the disease. alpha-Synuclein is enriched in the presynapse, but its synaptic targets are unknown. Synphilin-1 associates in vivo with alpha-synuclein promoting the formation of intracellular inclusions. Additionally synphilin-1 has been found to be an intrinsic component of Lewy bodies in patients with Parkinson's disease. To understand the role of synphilin-1 in Parkinson's disease, we sought to define its localization and function in the brain. We now report that, like alpha-synuclein, synphilin-1 was enriched in neurons. In young rats, synphilin-1 was prominent in neuronal cell bodies but gradually migrated to neuropil during development. Immunoelectron microscopy of adult rat cerebral cortex demonstrated that synphilin-1 was highly enriched in presynaptic nerve terminals. Synphilin-1 co-immunoprecipitated with synaptic vesicles, indicating a strong association with these structures. In vitro binding experiments demonstrated that the N terminus of synphilin-1 robustly associated with synaptic vesicles and that this association was resistant to high salt washing but was abolished by inclusion of alpha-synuclein in the incubation medium. Our data indicated that synphilin-1 is a synaptic partner of alpha-synuclein, and it may mediate synaptic roles attributed to alpha-synuclein.
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PMID:Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by alpha-synuclein. 1195 99

Synphilin-1 has been shown to interact with alpha-synuclein, which in turn is associated with Parkinson's disease. However, the function of synphilin-1 is unknown. We have cloned mouse synphilin in an attempt to describe conserved and therefore likely functional domains. The deduced amino acid sequence of the protein shows extensive homology with its human counterpart, with greatest similarities in those regions that contain ankyrin-like motifs and the coiled-coil domain. Expression of mouse synphilin-1 across tissues is similar to its human counterpart and not limited to brain. The results show that the synphilin-1 sequence and expression patterns are conserved across species.
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PMID:Sequence conservation between mouse and human synphilin-1. 1195 31

Synphilin-1 interacts with alpha-synuclein, which has been implicated in the pathogenesis of Parkinson's disease (PD). By examination of their interactions quantitatively, with the use of the yeast two-hybrid beta-galactosidase assay, we find that the synuclein amino acid (aa) 1-65 region is sufficient for an interaction. A central domain of synphilin-1, aa 349-555, is both necessary and sufficient for an interaction with alpha-synuclein. We did not observe an effect of the synuclein A53T mutation, which causes one familial form of PD, on interactions with synphilin-1. However, the A30P mutation caused an increase in the interaction between the synuclein aa 1-65 fragment and the synphilin-1 central domain.
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PMID:Analysis of synphilin-1 and synuclein interactions by yeast two-hybrid beta-galactosidase liquid assay. 1204 36

Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an alpha-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.
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PMID:Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease. 1276 Oct 37

Parkinson's disease is a common neurodegenerative disorder characterized by loss of dopaminergic neurons and appearance of Lewy bodies, cytoplasmic inclusions that are highly enriched with ubiquitin. Synphilin-1, alpha-synuclein, and Parkin represent the major components of Lewy bodies and are involved in the pathogenesis of Parkinson's disease. Synphilin-1 is an alpha-synuclein-binding protein that is ubiquitinated by Parkin. Recently, a mutation in the synphilin-1 gene has been reported in patients with sporadic Parkinson's disease. Although synphilin-1 localizes close to synaptic vesicles, its function remains unknown. To investigate the proteins that interact with synphilin-1, the present study performed a yeast two-hybrid screening and identified a novel interacting protein, Siah-1 ubiquitin ligase. Synphilin-1 and Siah-1 proteins were endogenously expressed in the central nervous system and were found to coimmunoprecipitate each other in rat brain homogenate. Confocal microscopic analysis revealed colocalization of both proteins in cells. Siah-1 was found to interact with the N terminus of synphilin-1 through its substrate-binding domain and to specifically ubiquitinate synphilin-1 via its RING finger domain. Siah-1 facilitated synphilin-1 degradation via the ubiquitin-proteasome pathway more efficiently than Parkin. Siah-1 was found to not facilitate ubiquitination and degradation of wild type or mutant alpha-synuclein. Synphilin-1 inhibited high K+-induced dopamine release from PC12 cells. Siah-1 was found to abrogate the inhibitory effects of synphilin-1 on dopamine release. Such findings suggest that Siah-1 might play a role in regulation of synphilin-1 function.
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PMID:Siah-1 facilitates ubiquitination and degradation of synphilin-1. 1450 61

Alpha-synuclein is a phosphoprotein that accumulates as a major component of Lewy bodies in the brains of patients with Parkinson disease. Synphilin-1, which is also present in Lewy bodies, binds with alpha-synuclein and forms cytoplasmic inclusions in transfected cells. Yet the molecular determinants of this protein-protein interaction are unknown. Here we report that casein kinase II (CKII) phosphorylates synphilin-1 and that the beta subunit of this enzyme complex binds to synphilin-1. Additionally, both CKII alpha and beta subunits are present within cytoplasmic inclusions in cells that overexpress synphilin-1. Notably, the interaction between synphilin-1 and alpha-synuclein is markedly dependent on phosphorylation. Inhibition of CKII activity by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole blocks the binding between these two proteins and significantly reduces the percentage of cells that contain eosinophilic cytoplasmic inclusions. Mutation of the major CKII phosphorylation site in alpha-synuclein (S129A) has no significant impact on the binding between alpha-synuclein and synphilin-1 or on the formation of synphilin-1/alpha-synuclein-positive inclusions. These data suggest that the CKII-mediated phosphorylation of synphilin-1 rather than that of alpha-synuclein is critical in modulating their tendency to aggregate into inclusions. These observations collectively indicate that a ubiquitous post-translational modification such as phosphorylation can regulate inclusion body formation in the context of alpha-synuclein and synphilin-1 interaction.
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PMID:Casein kinase II-mediated phosphorylation regulates alpha-synuclein/synphilin-1 interaction and inclusion body formation. 1464 18


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