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)

The synuclein family includes three known proteins: alpha-synuclein, beta-synuclein and gamma-synuclein. beta-Synuclein inhibits the aggregation of alpha-synuclein, a protein involved in Parkinson's disease. We have cloned and characterized the cDNA sequence for porcine beta-synuclein (SNCB) from pig cerebellum using RT-PCR. Expression analysis by quantitative RT-PCR demonstrated that SNCB transcripts were highly abundant in brain tissues. SNCB mRNA was also detected early in embryogenesis and significant increases in transcript levels were observed in several brain tissues during embryo development. Radiation hybrid mapping data indicate that the porcine SNCB maps to the q arm of chromosome 2 (2q21-22). The subcellular localization of recombinant porcine beta-synuclein was determined in three different cell types and shown to be cytoplasmic.
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PMID:Molecular cloning, characterization and developmental expression of porcine beta-synuclein. 1934 35

Parkinson's disease (PD) is a slowly progressive movement disorder that results from the loss of dopaminergic neurons in the substantia nigra, a small area of cells in the mid-brain. PD is a multifactorial disorder with unknown etiology, in which both genetic and environmental factors play important roles. Substantial evidence links alpha-synuclein, a small highly conserved presynaptic protein with unknown function, to both familial and sporadic PD. Rare familial cases of PD are associated with missense point mutations in alpha-synuclein, or with the hyper-expression of the wild type protein due to its gene duplication/triplication. Furthermore, alpha-synuclein was identified as the major component of amyloid fibrils found in Lewy body and Lewy neurites, the characteristic proteinaceous deposits that are the diagnostic hallmarks of PD. alpha-Synuclein is abundant in various regions of the brain and has two closely related homologs, beta-synuclein and gamma-synuclein. When isolated in solution, the protein is intrinsically disordered, but in the presence of lipid surfaces alpha-synuclein adopts a highly helical structure that is believed to mediate its normal function(s). A number of different conformational states of alpha-synuclein have been observed. Besides the membrane-bound form, other critical conformations include a partially-folded state that is a key intermediate in aggregation and fibrillation, various oligomeric species, and fibrillar and amorphous aggregates. A number of intrinsic and extrinsic factors that either accelerate or inhibit the rate of alpha-synuclein aggregation and fibrillation in vitro are known. There is a strong correlation between the conformation of alpha-synuclein (induced by various factors) and its rate of fibrillation. The aggregation process appears to be branched, with one pathway leading to fibrils and another to oligomeric intermediates that may ultimately form amorphous deposits. The molecular basis of Parkinson's disease appears to be tightly coupled to the aggregation of alpha-synuclein and the factors that affect its conformation. This review focuses on the contributions of Prof. Anthony L. Fink to the field and presents some recent developments in this exciting area.
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PMID:Biophysics of Parkinson's disease: structure and aggregation of alpha-synuclein. 1953 46

Many groups have generated alpha-synuclein (alpha-syn) transgenic (tg) mice as a rodent model for human synucleinopathies, including Parkinson's disease and dementia with Lewy bodies (DLB). Indeed, some of the lines displayed limited evidence of neurodegeneration, such as alpha-syn deposits, compromised function of dopaminergic neurons, fibrillization of alpha-syn, and astrogliosis. However, none of them fully replicate the pathological features of synucleinopathies. To better understand the pathogenesis of the synucleinopathies and to develop new therapeutic strategies, improvement of the current version of alpha-syn tg mice may be required. We predict that beta-synuclein (beta-syn), the homologue of alpha-syn, might be a key molecule for this purpose. Although beta-syn is a neuroprotective molecule counteracting the alpha-syn pathology in tg mice, it was previously shown that both beta-syn and gamma-synuclein were associated with axonal pathology in the hippocampus of sporadic cases of Parkinson's disease and DLB. Furthermore, two missense mutations (P123H and V70M) of beta-syn were recently identified in DLB. These mutants of beta-syn were prone to aggregate in vitro and overexpression of these mutant beta-syn proteins in neuroblastoma cells resulted in enhanced lysosomal pathology. Taken together, these results suggest that a toxic gain of function of beta-syn might be involved in the pathogenesis of synucleinopathies. In this context, it is of considerable interest to determine if mutant beta-syn-overexpressing tg mice could exhibit neuropathological features distinct from those in conventional alpha-syn tg mice. Furthermore, it is expected that a bigenic mouse model for mutant beta-syn/alpha-syn might be characterized by a more accelerated phenotype of synucleinopathies.
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PMID:Neurotoxic conversion of beta-synuclein: a novel approach to generate a transgenic mouse model of synucleinopathies? 1971 Nov 18

The high incidence of depression in Parkinson's disease (PD) has been well documented in the clinic; however, the underlying molecular mechanisms of these overlapping pathologies remain elusive. Using a rodent model of depression, the Wistar-Kyoto (WKY) rat, we previously demonstrated that in the frontal cortex the altered expression and protein interactions of alpha- and gamma-synuclein (alpha-Syn, gamma-Syn) were associated with dysregulated trafficking of the norepinephrine transporter (NET). Chronic treatment with desipramine (DMI), a NET-selective antidepressant, caused a disappearance of depressive-like behavior that was accompanied by a change in alpha-Syn and gamma-Syn expression and their trafficking of NET. Using this same model, we examined the expression of NET, alpha-Syn and gamma-Syn in the hippocampus, amygdale, brainstem, and striatum, all regions implicated in the development or maintenance of depression or PD pathology. Following chronic treatment with DMI, we observed a significant decrease in NET in the hippocampus, amygdala, and brainstem; decrease in gamma-Syn in the hippocampus and amygdala; and, increase in alpha-Syn in the hippocampus and amygdala. Unexpectedly, we observed a significant decrease in alpha-Syn expression in the striatum of the WKY following chronic DMI treatment. The altered expression of NET, alpha-Syn and gamma-Syn in different brain suggest that DMI's ability to improve depressive-like behavior in a rodent is associated with region-specific changes in the regulation of NET by alpha- and gamma-Syn.
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PMID:Desipramine induced changes in the norepinephrine transporter, alpha- and gamma-synuclein in the hippocampus, amygdala and striatum. 1981 34

alpha-Synuclein is a small presynaptic protein implicated in the pathogenesis of Parkinson disease. Nevertheless, its physiological roles and mechanisms remain incompletely understood. alpha-Synuclein is not only expressed in neurons but also in the vascular endothelium, which contains intracellular granules called Weibel-Palade bodies (WPBs) that contain a number of chemokines, adhesive molecules, and inflammatory cytokines. This study explored whether the exocytosis of WPB is regulated by alpha-synuclein. Phorbol 12-myristate 13-acetate-, thrombin-, or forskolin-induced von Willebrand factor release or translocation of P-selectin from endothelial cells were inhibited by alpha- and beta-synuclein but not gamma-synuclein. Three point mutants (A30P, A53T, and E46K) found in familial Parkinson disease also inhibited WPB exocytosis similar to that of wild-type alpha-synuclein. Furthermore, the negative regulation of WPB exocytosis required the N terminus or the nonamyloid beta-component of Alzheimer disease amyloid region of alpha-synuclein, but not the C-terminal acidic tail, and alpha-synuclein affected WPB exocytosis through interference with RalA activation by enhancing the interaction of RalGDS-beta-arrestin complexes. Immuno-EM analysis revealed that alpha-synuclein was localized close to WPBs. These findings imply that alpha-synuclein plays as a negative regulator in WPB exocytosis in endothelial cells.
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PMID:Regulation of Weibel-Palade body exocytosis by alpha-synuclein in endothelial cells. 2044 34

The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- and gamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication.
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PMID:Deletion of alpha-synuclein decreases impulsivity in mice. 2214 76

Synaptic re-uptake of dopamine is dependent on the dopamine transporter (DAT), which is regulated by its distribution to the cell surface. DAT trafficking is modulated by the Parkinson's disease-linked protein alpha-synuclein, but the contribution of synuclein family members beta-synuclein and gamma-synuclein to DAT trafficking is not known. Here we use SH-SY5Y cells as a model of DAT trafficking to demonstrate that all three synucleins negatively regulate cell surface distribution of DAT. Under these conditions the synucleins limit export of DAT from the endoplasmic reticulum (ER) by impairment of the ER-Golgi transition, leading to accumulation of DAT in this compartment. This mechanism for regulating DAT export indirectly through effects on ER and Golgi function represents a previously unappreciated role for the extended synuclein family that is likely applicable to trafficking of the many proteins that rely on the secretory pathway.
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PMID:Synucleins antagonize endoplasmic reticulum function to modulate dopamine transporter trafficking. 2396 27

Over the last decade, many genetic studies have suggested that the synucleins, which are small, natively unfolded proteins, are closely related to Parkinson's disease and cancer. Less is known about the molecular basis of this role. A comprehensive analysis of the evolutionary path of the synuclein protein family may reveal the relationship between evolutionarily conserved residues and protein function or structure. The phylogeny of 252 unique synuclein sequences from 73 organisms suggests that gamma-synuclein is the common ancestor of alpha- and beta-synuclein. Although all three sub-families remain highly conserved, especially at the N-terminal, nearly 15% of the residues in each sub family clearly diverged during evolution, providing crucial guidance for investigations of the different properties of the members of the superfamily. His50 is found to be an alpha-specific conserved residue (91%) and, based on mutagenesis, evolutionarily developed a secondary copper binding site in the alpha synuclein family. Surprisingly, this site is located between two well-known polymorphisms of alpha-synuclein, E46K and A53T, which are linked to early-onset Parkinson's disease, suggesting that the mutation-induced impairment of copper binding could be a mechanism responsible for alpha-synuclein aggregation.
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PMID:Evolutionary aspects of the synuclein super-family and sub-families based on large-scale phylogenetic and group-discrimination analysis. 2414 56

Synucleins belong to a family of intrinsically unstructured proteins that includes alpha-synuclein (aSyn), beta-synuclein (bSyn) and gamma-synuclein (gSyn). aSyn is the most studied member of the synuclein family due to its central role in genetic and sporadic forms of Parkinson's disease and other neurodegenerative disorders known as synucleionopathies. In contrast, bSyn and gSyn have been less studied, but recent reports also suggest that, unexpectedly, these proteins may also cause neurotoxicity. Here, we explored the yeast toolbox to investigate the cellular effects of bSyn and gSyn. We found that bSyn is toxic and forms cytosolic inclusions that are similar to those formed by aSyn. Moreover, we found that bSyn shares similar toxicity mechanisms with aSyn, including vesicular trafficking impairment and induction of oxidative stress. We demonstrate that co-expression of aSyn and bSyn exacerbates cytotoxicity, due to increased dosage of toxic synuclein forms, and that they are able to form heterodimers in both yeast and in human cells. In contrast, gSyn is not toxic and does not form inclusions in yeast cells. Altogether, our findings shed light into the question of whether bSyn can exert toxic effects and confirms the occurrence of aSyn/bSyn heterodimers, opening novel perspectives for the development of novel strategies for therapeutic intervention in synucleinopathies.
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PMID:Yeast reveals similar molecular mechanisms underlying alpha- and beta-synuclein toxicity. 2658 32


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