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)

Mutations in alpha-synuclein have been identified in some rare families with autosomal dominant Parkinson's disease (PD). The synuclein gene family shares physical and functional homology with 14-3-3 proteins and binds to 14-3-3 proteins and to its ligands. We therefore investigated whether 14-3-3 proteins are also involved in the pathogenesis of PD. Here we demonstrate that 14-3-3 proteins are colocalized with Lewy bodies in PD. We investigated the 14-3-3 eta (YWHAH) gene by mutation analysis and association studies as it maps to human chromosome 22q12.1-q13.1, a region which has been recently implicated in PD and carried out immunohistochemical studies of Lewy bodies with two different 14-3-3 eta antibodies. In 358 sporadic and familial PD patients, disease causing mutations were not identified. Furthermore, association studies with intragenic polymorphisms do not provide evidence for an involvement of 14-3-3 eta in the pathogenesis of PD. In accordance with these findings, there was no staining of substantia nigra Lewy bodies with antibodies specific for the 14-3-3 eta subunit.
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PMID:14-3-3 protein is a component of Lewy bodies in Parkinson's disease-mutation analysis and association studies of 14-3-3 eta. 1248 Jan 76

Intraneuronal deposition of alpha-synuclein as fibrils and oxidative stress are both implicated in the pathogenesis of Parkinson's disease. We found that the critical rate-limiting step in nucleation of alpha-synuclein fibrils under physiological conditions is the oxidative formation and accumulation of a dimeric, dityrosine cross-linked prenucleus. Dimer formation is accelerated for the pathogenic A30P and A53T mutant alpha-synucleins, because of their greater propensity to self-interact, which is reflected in the smaller values of the osmotic second virial coefficient compared to that of wild-type synuclein. Our finding that oxidation is an essential step in alpha-synuclein aggregation supports a mechanism of Parkinson's disease pathogenesis in which the separately studied pathogenic factors of oxidative stress and alpha-synuclein aggregation converge at the critical step of alpha-synuclein dimer formation.
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PMID:Oxidative dimer formation is the critical rate-limiting step for Parkinson's disease alpha-synuclein fibrillogenesis. 1253 96

Mutations in the gene encoding alpha-synuclein (alpha-syn) have recently been linked to rare hereditary forms of Parkinson's disease. A yeast two-hybrid screen with alpha-synuclein (alpha-syn) identified synphilin as an alpha-syn-interacting protein, potentially implicating synphilin in the pathogenesis of synucleinopathies. Co-transfection of synphilin and the central (NAC) region of alpha-syn in HEH293 cells resulted in synuclein inclusions. Furthermore, synphilin immunoreactivity has been observed in Lewy bodies (LBs) and glial cytoplasmic inclusions of synucleinopathies. To further characterize synphilin, we utilized two new anti-synphilin antibodies for biochemical and immunohistochemical studies in normal and disease brain tissues. In normal brain tissue, synphilin localized predominantly to large neurons, such as substantia nigra neurons, hippocampal pyramidal and cerebellar Purkinje cells. However, in a few pathological cases synphilin immunoreactivity was present in glial cells and a small percentage of cortical and nigral LBs. In brain extracts, synphilin was observed primarily as a 90-kDa band but protein bands of 50 and 65 kDa were also present in both soluble (high salt) and lipid (Triton X-100) fractions. Additionally, less abundant higher molecular mass species, including a 120-kDa band of similar size to that of synphilin expressed in transiently transfected cells were recovered in 8 M urea-solubilized pellets after sequential extraction of brain tissue with buffers of increasing strengths. The presence of the synphilin of higher molecular mass was detected regardless of alpha-syn pathology and may represent an immature form of synphilin. Thus, although synphilin may be an alpha-syn-interacting protein present in some alpha-syn lesions, it still remains to be determined whether synphilin plays a critical role in mechanisms of brain degeneration in human synucleinopathies.
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PMID:Synphilin in normal human brains and in synucleinopathies: studies with new antibodies. 1253 29

Alpha-synuclein is a neuronal protein thought to be central in the pathogenesis of Parkinson's disease (PD) because it comprises the fibrillar core of Lewy bodies, one of the histologically defining lesions of PD, and because mutations in alpha-synuclein cause autosomal dominant PD. Although its physiologic role is uncertain, alpha-synuclein is a synaptic protein that may contribute to plasticity. We produced synuclein with incorporated photoprobes to identify and purify novel synuclein-interacting proteins both to begin to clarify the physiology of synuclein and to identify factors that may regulate synuclein conformation. We detected several cross-links and purified and identified one as calmodulin (CaM). CaM binds to both wild type and PD-associated mutant alpha-synucleins in a calcium-dependent manner. We further demonstrate that CaM and alpha-synuclein interact in intact cells in a calcium-dependent manner and that activated CaM accelerates the formation of synuclein fibrils in vitro. We hypothesize that the known calcium control of synuclein function is mediated through CaM interaction and that CaM potentially alters synuclein conformation.
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PMID:Parkinson's disease-associated alpha-synuclein is a calmodulin substrate. 1261

alpha-Synuclein accumulates in Lewy bodies and two missense mutations, A30P and A53T, have been linked to familial Parkinson's disease. Neither the normal function of alpha-synuclein nor the pathomechanism of alpha-synuclein-induced neuropathy are known. SK-N-MC neuroblastoma cells were transiently transfected with either wt alpha-synuclein, or its mutants, and their abilities to protect against oxidative stress were assessed. At low expression levels (1 microg cDNA/10(5) cells), all three synuclein variants were devoid of any effect on dopamine-induced cytotoxicity and nitrite production, whereas at higher expression (5 microg cDNA/10(5) cells), the variants enhanced dopamine-mediated effects. Low levels of wt alpha-synuclein blocked H(2)O(2)-induced cytotoxicity and nitrite production, a protective effect that was partly decreased upon higher expression. Both A30P and A53T increased in a dose-dependent manner H(2)O(2)-induced nitrite production and cell death. These results show an absence of protective effects for the A30P/A53T mutants, and a differential cytoprotective role of alpha-synuclein against oxidants, which varies according to expression levels.
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PMID:Differential cytotoxicity of dopamine and H2O2 in a human neuroblastoma divided cell line transfected with alpha-synuclein and its familial Parkinson's disease-linked mutants. 1272 33

Following the identification of mutations in alpha-synuclein as the cause of some rare forms of familial Parkinson's disease (PD), genetic research has uncovered numerous gene loci of PD. Meanwhile, several neurodegenerative diseases have been shown to accumulate a-synuclein in neuronal and glial cells summarizing this group of diseases as synucleinopathies. All currently known gene defects causing PD alter the ubiquitin-proteasomal pathway of protein degradation. Identification of these disease mutations allows studying the functional consequences which lead to cellular dysfunction and cell death in cell culture and transgenic animal models, to identify therapeutic targets and to test potential protective strategies in these models.
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PMID:Therapeutic strategies for Parkinson's disease based on data derived from genetic research. 1276 28

alpha-Synuclein accumulation plays an important role in the pathogenesis of Lewy body disease (LBD) and Parkinson's disease (PD). Although the mechanisms are not yet clear, it is possible that dysregulation of the extracellular signal-regulated kinase (ERK) might play a role. As caveolins form scaffolds onto which signaling molecules such as ERK can assemble, we propose that signaling alterations associated with alpha-synuclein accumulation and neurodegeneration, might be mediated via caveolae. Therefore, the objective of the present study was to investigate the potential contribution of alterations in the caveolar system in mediating alpha-synuclein effects on the ERK signaling pathway. For this, synuclein-transfected B103 neuroblastoma cells were used as a model system. In this cell line, caveolin-1 expression was up-regulated, whereas, ERK was down-regulated. ERK was weakly but consistently co-immunoprecipitated with alpha-synuclein but caveolin-1 did not co-immunoprecipitate with alpha-synuclein. Moreover, treatment of alpha-synuclein- overexpressing cells with caveolin-1 antisense oligonucleotides resulted in stimulation of ERK activity, with amelioration of the neuritic alterations. Transduction of alpha-synuclein-overexpressing cells, with an adenoviral vector directing the expression of ERK, resulted in suppression of caveolin-1 expression and re-establishment of the normal patterns of neurite outgrowth. These results suggest that alpha-synuclein may also interfere with ERK signaling by dysregulating caveolin-1 expression. Thus, the caveolin-1/ERK pathway could be a therapeutic target for the alpha-synuclein-related neurodegenerative disorders.
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PMID:Alpha-synuclein up-regulates expression of caveolin-1 and down-regulates extracellular signal-regulated kinase activity in B103 neuroblastoma cells: role in the pathogenesis of Parkinson's disease. 1278 66

We have used NMR spectroscopy and limited proteolysis to characterize the structural properties of the Parkinson's disease-related protein alpha-synuclein in lipid and detergent micelle environments. We show that the lipid or micelle surface-bound portion of the molecule adopts a continuously helical structure with a single break. Modeling alphaS as an ideal alpha-helix reveals a hydrophobic surface that winds around the helix axis in a right-handed fashion. This feature is typical of 11-mer repeat containing sequences that adopt right-handed coiled coil conformations. In order to bind a flat or convex lipid surface, however, an unbroken helical alphaS structure would need to adopt an unusual, slightly unwound, alpha11/3 helix conformation (three complete turns per 11 residues). The break we observe in the alphaS helix may allow the protein to avoid this unusual conformation by adopting two shorter stretches of typical alpha-helical structure. However, a quantitative analysis suggests the possibility that the alpha11/3 conformation may in fact exist in lipid-bound alphaS. We discuss how structural features of helical 11-mer repeats could play a role in the reversible lipid binding function of alpha-synuclein and generalize this argument to include the 11-mer repeat-containing apolipoproteins, which also require the ability to release readily from lipid surfaces. A search of protein sequence databases confirms that synuclein-like 11-mer repeats are present in other proteins that bind lipids reversibly and predicts such a role for a number of hypothetical proteins of unknown function.
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PMID:A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins. 1278 76

The etiology of Parkinson's disease (PD) has yet to be delineated. Human genetic studies as well as neurotoxicant and transgenic animal models of PD suggest that multiple events trigger the initiation of this progressive age-related neurodegenerative disorder. In addition, we propose that despite disparate disease triggers a convergent pathobiologic pathway exists leading to cell death. The common pathway model posits that both familial and sporadic forms of Parkinson's disease obligately share a common pathophysiological substrate. Herein we discuss the evidence for a common pathway model of Parkinson's disease through a review of synuclein transgenic models and outline an approach for the identification of shared therapeutic targets. We end with a discussion of a potential alternative therapy for Parkinson's disease.
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PMID:Convergent pathobiologic model of Parkinson's disease. 1284 84

Synucleins are emerging as central player in the fundamental neural processes and in the formation of pathologically insoluble deposits characteristic of Alzheimer's disease and Parkinson's disease. However, gamma Synuclein (SNCG) is also highly associated with breast cancer and ovarian cancer progression. Whereas most studies of this group of proteins have been directed to the elucidation of their role in the formation of depositions in brain tissue, the normal cellular function of this highly conserved synuclein family remains largely unknown. A notable finding in this study is that SNCG, identified previously as a breast cancer-specific gene 1, strongly stimulated the ligand-dependent transcriptional activity of estrogen receptor-alpha (ER-alpha) in breast cancer cells. Augmentation of SNCG expression stimulated transcriptional activity of ER-alpha, whereas compromising endogenous SNCG expression suppressed ER-alpha signaling. The SNCG-stimulated ER-alpha signaling was demonstrated in three different cell systems including ER-alpha-positive and SNCG-negative MCF-7 cells, ER-alpha-positive and SNCG-positive T47D cells, and SNCG-negative and ER-alpha-negative MDA-MB-435 cells. The SNCG-mediated stimulation of ER-alpha transcriptional activity is consistent with its stimulation of the ligand-dependent cell growth. Whereas overexpression of SNCG stimulated the ligand-dependent cell proliferation, suppression of endogenous SNCG expression significantly inhibited cell growth in response to estrogen. The stimulatory effect of SNCG on ERalpha-regulated gene expression and cell growth can be effectively inhibited by antiestrogens. These data indicate that SNCG is required for efficient ER-alpha signaling and, thus, stimulated hormone-responsive mammary tumors.
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PMID:Stimulation of estrogen receptor signaling by gamma synuclein. 1287 81


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