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)

Many neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are now characterized by abnormal accumulation of certain proteins in the brain. The key molecules include amyloid beta-protein (Abeta), tau and a-synuclein, all of which are involved in the pathogenesis and provide histopathological hallmarks of the diseases. Abeta is continuously produced in and removed from the brain. Microglia and astrocytes take up and degrade soluble Abeta. In the Alzheimer brain, once-deposited, insoluble Abeta is also removed by phagocytosis by activated microglia. The success of these removal processes, however, is at best partial. The phagocytic removal of insoluble Abeta is associated with neuroinflammation, a potentially neurotoxic reaction. Tau is accumulated in astrocytes under a diversity of pathological conditions in several forms: thorn-shaped astrocytes; tuft-shaped astrocytes; astrocytic plaques. Thorn-shaped astrocytes are associated with gliosis and are not disease-specific. Tuft-shaped astrocytes are characteristic of progressive supranuclear palsy (PSP) and astrocytic plaques of cortico-basal degeneration (CBD). Tau accumulation in oligodendrocytes is referred to as coiled bodies and occurs in PSP, CBD, Pick's disease and some other so-called taupathies. a-Synuclein is accumulated in oligodendrocytes, which is referred to as glial cytoplasmic inclusions (GCI). Occurrence of GCI is diagnostic to multiple system atrophy. Transgenic mouse models in which tau or alpha-synuclein is overexpressed in glial cells indicate that neuronal degeneration occurs following tau/alpha-synuclein accumulation in glial cells, supporting a notion that these abnormal glial cells play pathogenic roles.
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PMID:[Abeta, tau and alpha-synuclein and glial cells]. 1663 93

gamma-Synuclein is a member of the synuclein family consisting of three proteins. Within the last several years increasing attention has focused on these proteins because of their role in human diseases. alpha-Synuclein relevance to Parkinson's disease is based on mutations found in familial cases of the disease and its presence in filaments and inclusion bodies in sporadic cases. gamma-Synuclein is implicated in some forms of cancer and ocular diseases, while beta-synuclein may antagonize their pathological functions. In this paper we present data on the localization and properties of gamma-synuclein in several neuronal and nonneuronal cell cultures. We show that contrary to the current opinion, gamma-synuclein is not an exclusively cytoplasmic protein, but has a dynamic localization and can associate with subcellular structures. It is present in the perinuclear area and may be associated to centrosomes. On late steps of mitosis gamma-synuclein is not found in the centrosomes, and redistributes to the midbody in telophase. Under stress conditions a translocation of gamma-synuclein from the perinuclear area to the nucleus occurs exhibiting nucleocytoplasmic shuttling. gamma-Synuclein overexpression reduces neurite outgrowth in a greater extent then alpha-synuclein overexpression. These data support the view that gamma-synuclein may change its intracellular localization and associate with subcellular structures in response to intracellular signaling or stress.
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PMID:gamma-synuclein has a dynamic intracellular localization. 1673 59

A comprehensive, unbiased inventory of synuclein forms present in Lewy bodies from patients with dementia with Lewy bodies was carried out using two-dimensional immunoblot analysis, novel sandwich enzyme-linked immunosorbent assays with modification-specific synuclein antibodies, and mass spectroscopy. The predominant modification of alpha-synuclein in Lewy bodies is a single phosphorylation at Ser-129. In addition, there is a set of characteristic modifications that are present to a lesser extent, including ubiquitination at Lys residues 12, 21, and 23 and specific truncations at Asp-115, Asp-119, Asn-122, Tyr-133, and Asp-135. No other modifications are detectable by tandem mass spectrometry mapping, except for a ubiquitous N-terminal acetylation. Small amounts of Ser-129 phosphorylated and Asp-119-truncated alpha-synuclein are present in the soluble fraction of both normal and disease brains, suggesting that these Lewy body-associated forms are produced during normal metabolism of alpha-synuclein. In contrast, ubiquitination is only detected in Lewy bodies and is primarily present on phosphorylated synuclein; it therefore likely occurs after phosphorylated synuclein has deposited into Lewy bodies. This invariant pattern of specific phosphorylation, truncation, and ubiquitination is also present in the detergent-insoluble fraction of brain from patients with familial Parkinson's disease (synuclein A53T mutation) as well as multiple system atrophy, suggesting a common pathogenic pathway for both genetic and sporadic Lewy body diseases. These observations are most consistent with a model in which preferential accumulation of normally produced Ser-129 phosphorylated alpha-synuclein is the key event responsible for the formation of Lewy bodies in various Lewy body diseases.
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PMID:Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. 1684 63

Excessive accumulation of alpha synuclein (a-syn) in the brain has been implicated in several degenerative neurological disorders, most notably Parkinson's disease. The aggregation of a-syn is the major component of intraneuronal inclusions, Lewy bodies, which are neuropathological features, observed in Parkinson's disease, Lewy body dementia, and other synucleopathies. Diverse cellular events can contribute to a-syn accumulation, aggregation, and to subsequent Lewy body formation. These factors include genetic mutations of synuclein, parkin, or the deubiquitinating enzyme, ubiquitin C-terminal hydrolase (UCH-L1), leading to reduced clearance of a-syn by the ubiquitin proteasomal pathway (UPP). Furthermore, intracellular insults include environmental factors and an age-related decrement in antioxidant defense systems that increase oxidative stress and can affect either the accumulation or clearance of a-syn. We have dynamically modeled a-syn processing in normal and in several disease states; focusing upon alterations in the aggregation and clearance of a-syn as influenced by the UPP and the oxidative stress pathways. Simulation of increased oxidative stress generates a free radical profile analogous to that reported in vivo following exposure to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Varying model parameters of oxidative stress, UPP dysfunction, or both pathways, simulate kinetics of a-syn that corresponds with the neuropathology described for the sporadic and genetic forms of Parkinson's disease. This in silico model provides a mathematical framework that enables kinetic appraisal of pathway components to better identify and validate important pharmacological targets.
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PMID:Dynamic modeling of alpha-synuclein aggregation for the sporadic and genetic forms of Parkinson's disease. 1692 Feb 72

Parkinson's disease (PD) is a common neurodegenerative disease of unknown etiology. Evidence suggests a role for protein misfolding in disease pathogenesis. One pathologic feature observed in dopaminergic neurons is the intracytoplasmic eosinophilic inclusions known as Lewy bodies. One component of Lewy bodies, the presynaptic protein, alpha-synuclein forms oligomers and higher order aggregates and is proposed to be involved in dopaminergic neuronal death. In an effort to discriminate between alpha-synuclein conformational forms as well as design potential disruptors of pathogenic misfolding we panned a human phage antibody library for anti-synuclein single chain antibodies (scFvs). We identified six scFvs which recognize different conformers of alpha-synuclein in both an ELISA and Western blot analysis. These scFvs may further our understanding of alpha-synuclein's role in PD.
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PMID:Identification of human alpha-synuclein specific single chain antibodies. 1697 26

Several recent observations suggest a connection between Gaucher disease, the inherited deficiency of glucocerebrosidase, and the synucleinopathies. Rare patients have been observed who develop both Gaucher disease and parkinsonism. Autopsy studies on these subjects reveal synuclein-positive Lewy bodies and inclusions. An increased incidence of synucleinopathies also has been noted in relatives of Gaucher probands. In complementary studies, screening of patients with parkinsonism has identified a greater than expected frequency of glucocerebrosidase mutations. These glucocerebrosidase mutation carriers have a wide spectrum of associated parkinsonian phenotypes, ranging from classic L-dopa-responsive Parkinson disease to a phenotype more characteristic of Lewy body dementia. Despite this association, the vast majority of Gaucher carriers and patients with Gaucher disease never develop parkinsonism. However, mutations in this gene are likely to be a contributing risk factor in subjects otherwise prone to developing synucleinopathies.
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PMID:Gaucher disease and the synucleinopathies. 1704 14

Synucleins are proteins known for their malfunction in a group of illnesses called synucleopathies, which includes Alzheimer's and Parkinson's disease. To learn more about the role of synucleins in the CNS, we have studied levels of message coding for alpha-, beta-, and gamma-synuclein using quantitative RT-PCR. Levels of synuclein mRNAs were studied in the cerebral cortex (left and right, anterior and posterior), hippocampus, striatum, and cerebellum, obtained from 5-d-old (newborn), 1-mo (juvenile)-, and 6-, and 9-mo (adult)-old rats. The mRNA levels for all synucleins varied significantly among structures. The rank order of mRNA levels in different structures was cortex = hippocampus > striatum > cerebellum for alpha-synuclein; cortex > hippocampus = cerebellum > striatum for beta-synuclein; and hippocampus = striatum > cortex = cerebellum for gamma-synuclein. There was significant effect of age for mRNA levels for all synucleins. The dynamics of these changes were different depending on type of synuclein and brain structure. Levels of mRNA for alpha-synuclein were significantly reduced with age in all structures except hippocampus. For beta- and gamma-synuclein, levels increased significantly only in the cerebral cortex and only from 5 d to 1 mo of age. In contrast, gamma-synuclein levels in the cerebellum were very high at 5 d and significantly reduced at 1 mo of age. The revealed pattern and dynamics of changes in the levels of mRNA coding for synucleins would support the conclusion for an important role of these molecules during development and the aging process.
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PMID:Levels of mRNA coding for alpha-, beta-, and gamma-synuclein in the brains of newborn, juvenile, and adult rats. 1708 84

alpha-synuclein gene mutations are major underlying genetic defects known in familial juvenile onset Parkinson's disease (PD), and alpha-synuclein is a major constituent of Lewy Bodies, the pathological hallmark of PD. The normal cellular function of alpha-synuclein has been elusive, and its exact etiological mechanism in causing dopaminergic neuronal death in PD is also not clearly understood. Very recent reports now indicate that mutant or simply over-expressed alpha- synuclein could cause damage by interfering with particular steps of neuronal membrane traffic. alpha-synuclein selectively blocks endoplamic reticulum-to-Golgi transport, thus causing ER stress. A screen in a yeast revealed that alpha- synuclein toxicity could be suppressed by over-expression of the small GTPase Ypt1/Rab1, and that over-expression of the latter rescues neuron loss in invertebrate and mammalian models of alpha-synuclein-induced neurodegeneration. alpha-synuclein may also serve a chaperone function for the proper folding of synaptic SNAREs that are important for neurotransmitter release. We discuss these recent results and the emerging pathophysiological interaction of alpha-synuclein with components of neuronal membrane traffic.
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PMID:alpha-synuclein and Parkinson's disease: the first roadblock. 1712 88

Single-chain Fv and single-domain antibodies retain the binding specificity of full-length antibodies but they can be cloned, selected, engineered, and manipulated as genes. When expressed intracellularly in mammalian cells these intracellular antibodies, or intrabodies, have the potential to alter the folding, interactions, modifications, or subcellular localization of their targets. These reagents have previously been developed as therapeutics against cancer and HIV. Since misfolded and accumulated intracellular proteins characterize several major neurodegenerative disorders, including Huntington disease (HD) and Parkinson disease, these disorders are prime candidates for intrabody therapy. In this article we review the extension of intrabody technology to the nervous system. Studies of HD have been used to develop the approach and anti-synuclein strategies are in the early stages of development. Such neurodegenerative diseases are therefore poised for engineered antibody approaches, which can provide a pipeline of novel therapeutics and new drug discovery tools.
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PMID:The therapeutic potential of intrabodies in neurologic disorders: focus on Huntington and Parkinson diseases. 1717 19

The discovery of three mutants in the -synuclein (alphaSyn) gene and the identification of alphaSyn as the major component of Lewy body have opened a new field for understanding the pathogenesis of Parkinson's disease (PD). AlphaSyn is a natively unfolded protein with unknown function and unspecified conformational heterogeneity. In this study, we introduce four Ser/Ala --> Cys mutations at positions 9, 42, 69, and 89 in human wild-type alphaSyn (wt-alphaSyn) and two PD-associated alphaSyn mutants, A30P-alphaSyn and A53T-alphaSyn. This allows expression of three alphaSyn mutants, wt-alphaSyn(4C), A30P-alphaSyn(4C), and A53T-Syn(4C). Subsequent oxidative folding enables each alphaSyn(4C) mutant to form three partially stabilized two-disulfide isomers, designated as alphaSyn(2SS), that are amenable to further isolation and characterization. These alphaSyn mutants exhibit the following properties. (a) A30P-alphaSyn(4C) exhibits a lower folding flexibility than wt-alphaSyn(4C) and A53T-alphaSyn(4C). (b) All three alphaSyn(4C) mutants, like wt-alphaSyn, exhibit a predominant structure of random coil. However, wt-alphaSyn(2SS) adopts an alpha-helical conformation, whereas A30P-alphaSyn(2SS) and A53T-alphaSyn(2SS) take on significant beta-sheet structure. (c) A30P-alphaSyn(2SS) shows a stronger tendency to aggregate than A53T-alphaSyn(2SS) and wt-alphaSyn(2SS). (d) Three isolated isomers of wt-alphaSyn(2SS) exhibit a propensity for forming oligomers different yet enhanced versus that for wt-alphaSyn. These data together substantiate the notion that under physiological conditions, human alphaSyn exists as diverse conformational isomers which exhibit distinct propensities for aggregation and fibril formation.
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PMID:Isomers of human alpha-synuclein stabilized by disulfide bonds exhibit distinct structural and aggregative properties. 1720 70


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