Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A key pathological feature of Alzheimer's disease (AD) is the formation and accumulation of amyloid fibers within the neurophil as senile plaques and in the walls of cerebral and meningeal blood vessels. The major component is the 39 to 42 residue amyloid beta protein (A beta), which is an internal proteolytic fragment of the membrane-associated amyloid precursor protein. Aggregation of A beta into amyloid fibers that could be cytotoxic may be a factor in the AD-related neuronal loss. To understand the steps and molecular interactions involved in the transition from a soluble to fibrous form of A beta, and to test molecular models that postulate ion pairing between beta-strands, we have synthetized four peptides having substitutions in specific, charged residues. These included an A beta fragment, residues 11 to 25, and having histidine-to-aspartate replacements at positions 13 (H13D) and 14 (H14D), an aspartate-to-lysine at position 23 (D23K) and a 28-mer full-length extracellular domain where the positive charge cluster at His13-His14-Gln15-Lys16 was replaced by an uncharged Gly13-Gly14-Gln15-Gly16 (GGQG). Fourier-transform infrared spectroscopy and fiber X-ray diffraction determined that the H13D and H14D substitutions had negligible effect on beta-sheet formation, suggesting that these residues are not critical for the intramolecular interactions necessary for folding in the beta-conformation. However, negative-stain electron microscopy revealed that the loss of the His13 or His14 resulted in only protofilament formation, suggesting that these residues are involved in amyloid fibril assembly. By contrast, the D23K substitution virtually eliminated folding into a beta-sheet conformation, with appreciable secondary structure being detected only following extended incubation times. The complete absence of the centrally charged region GGQG arrested amyloid assembly at the protofilament stage and also reduced the stability of the beta-conformation, suggesting a contribution of Lys16 in maintaining secondary structure. While it has been conclusively demonstrated by previous investigations that amyloid formation is dependent to a large extent on hydrophobically driven interactions, our results indicate that charge-charge interactions function in concert with non-ionic interactions to stabilize the beta-sheet conformation and assembly of AD amyloid fibers.
J Mol Biol 1994 Nov 18
PMID:Conformation and fibrillogenesis of Alzheimer A beta peptides with selected substitution of charged residues. 796 23

For the past 40 years, research into Parkinson's disease (PD) has been predominantly the province of epidemiologists interested in pursuing the connection between the disease and environmental factors such as viral infection or neurotoxins. Hereditary influences were actually discounted because of a high monozygotic twin discordance rate found in studies that were later shown to be inadequate and inconclusive. There has recently been a resurgence of interest in investigating hereditary factors in PD when it became more and more apparent that a positive family history was a major risk factor for the disease. Meanwhile, it also became increasingly apparent from neuropathological studies that the common, idiopathic form of Parkinson's disease had, in fact, a pathological correlate, i.e., the existence of Lewy bodies, an eosinophilic cytoplasmic inclusion body, distributed diffusely throughout the substantia nigra, hypothalamus, hippocampus, autonomic ganglia and olfactory tracts. Although candidate gene approaches to linkage in PD families have not been rewarding, a genome wide scan mapped PD to 4q21-23 in one large family with PD with diffuse Lewy bodies, where a candidate gene, alpha-synuclein, resides. This gene encodes a presynaptic protein of which a peptide fragment is known to be a constituent of Alzheimer's disease plaques. The identification of a missense mutation in the alpha-synuclein gene in four independent PD families suggests that at least some fraction of familial PD with diffuse Lewy bodies is the result of an abnormal protein that interferes with normal protein degradation leading to the development of inclusions and ultimately neuronal cell death. There may be common pathogenetic mechanisms involved in alpha-synuclein mutations in PD and beta-amyloid and presenilin gene mutations in Alzheimer's disease.
Hum Mol Genet 1997
PMID:Genetics of Parkinson's disease. 930 Jun 60

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha-synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha-synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.
Hum Mol Genet 1998 Apr
PMID:Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD). 949 30

In the past few years, the genetic contribution to Parkinson's disease (PD) has gained major attention and has resulted in the identification of the first mutant gene, called alpha-synuclein, involved in the pathogenesis of autosomal-dominant PD. alpha-Synuclein is a major component of Lewy bodies, which are a neuropathological feature of PD. Furthermore, deletions in the parkin gene have been identified as the primary cause in rare forms of autosomal-recessive juvenile PD. The elucidation of polygenic changes in the dopamine pathway, mitochondrial dysfunction, and metabolism of xenobiotics is now technically possible by means of association and genotype studies. The increasing knowledge of the pathogenesis of PD at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression.
Mol Med Today 1998 Oct
PMID:Genetic dissection of familial Parkinson's disease. 979 32

Aoffa-Synuclein, a presynaptic nerve terminal protein, may be an important component of Lewy bodies in Parkinson's disease, dementia with Lewy bodies, and other neurodegenerative diseases. Additionally, recent genetic studies based on linkage analysis and cosegregation of A53T and A30P missense mutations demonstrated that the alpha-synuclein gene may be responsible for the development of at least some cases of familial Parkinson's disease. Despite intense interest in the members of the synuclein family, their function(s) and exact role in the diseases remained unknown. Here we describe a new member of the synuclein family, which we term synoretin, and show that it is expressed in different retinal cells, as well as in the brain, and it may affect the regulation of signal transduction through activation of the Elk1 pathway.
Mol Cell Neurosci 1999 Feb
PMID:Synoretin--A new protein belonging to the synuclein family. 1019 68

Despite being considered the archetypal non-genetic neurological disorder, genetic analysis of Parkinson's disease has shown that there are at least three genetic loci. Furthermore, these analyses have suggested that the phenotype of the pathogenic loci is wider than simple Parkinson's disease and may include Lewy body dementia and some forms of essential tremor. Identification of alpha-synuclein as the first of the loci involved in Parkinson's disease and the identification of this protein in pathological deposits in other disorders has led to the suggestion that it may share pathogenic mechanisms with multiple system atrophy, Alzheimer's disease and prion disease and that these mechanisms are related to a synuclein pathway to cell death. Finally, genetic analysis of the synuclein diseases and the tau diseases may indicate that this synuclein pathway is an alternative to the tau pathway to cell death.
Hum Mol Genet 1999
PMID:The genetics of disorders with synuclein pathology and parkinsonism. 1046 43

Alpha-synuclein, a presynaptic protein of the central nervous system, has been implicated in the synaptic events such as neuronal plasticity during development and learning, and neuronal degeneration under pathological conditions. As an effort to understand the biological function of alpha-synuclein, we examined the expression patterns of alpha-synuclein in various human hematopoietic cells, and in Drosophila at different developmental stages. The alpha-synuclein was ubiquitously expressed in all the tested hematopoietic cells including T cells, B cells, NK cells, and monocytes, as well as in the lymphoma cell lines, Jurkat and K562. A potential alpha-synuclein homologue was also expressed in Drosophila, and its expression appeared to be temporally and spatially regulated during development. Our data suggest that alpha-synuclein may function in invertebrates as well as in vertebrates and its function may not be restricted to the neuron.
Mol Cells 2000 Feb 29
PMID:Expression patterns of alpha-synuclein in human hematopoietic cells and in Drosophila at different developmental stages. 1077 49

Mutations of the alpha-synuclein gene have been identified in autosomal dominant Parkinson's disease (PD). Transgenic mice overexpressing wild-type human alpha-synuclein develop motor impairments, intraneuronal inclusions and loss of dopaminergic terminals in the striatum. To study the mechanism of action through which mutant alpha-synuclein toxicity is mediated, we have generated stable, inducible cell models expressing wild-type or PD-associated mutant (G209A) alpha-synuclein in human-derived HEK293 cells. Increased expression of either wild-type or mutant alpha-synuclein resulted in the formation of cytoplasmic aggregates which were associated with the vesicular (including monoaminergic) compartment. Expression of mutant alpha-synuclein induced a significant increase in sensitivity to dopamine toxicity compared with the wild-type protein expression. These results provide an explanation for the preferential dopaminergic neuronal degeneration seen in both the PD G209A mutant alpha-synuclein families and suggest that similar mechanisms may underlie or contribute to cell death in sporadic PD.
Hum Mol Genet 2000 Nov 01
PMID:Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity. 1106 27

Synucleins comprise a family of small intracellular proteins that have recently attracted considerable attention because of their involvement in human diseases. Mutations of alpha-synuclein has been found in several families with hereditary early-onset Parkinson's disease and accumulation of this protein in characteristic cytoplasmic inclusions is a pathohistological hallmark of several neurodegenerative diseases that have been recently classified as 'alpha;-synucleinopathies' (reviewed in Brain Res. Bull. 50 (1999) 465; J. Neurosci. Res. 58 (1999) 120; Philos. Trans. R. Soc. Lond. Biol. Sci. 354 (1999) 1101; Brain Pathol. 9 (1999) 733). Aggregates of beta-synuclein and persyn (gamma-synuclein) also have been found in dystrophic neurites associated with Parkinson's and other neurodegenerative diseases (Proc. Natl. Acad. Sci. USA 96 (1999) 13450; and our unpublished observations). Moreover, persyn has been implicated in malignization of breast tumours (Cancer Res. 57 (1997) 759; Cancer Res. 59 (1999) 742; Hum. Mol. Genet. 7 (1998) 1417). All synucleins have distinct, although overlapping, patterns of expression in the embryonic, postnatal and adult mammalian nervous systems, suggesting important, although still not clear, biological functions in neuronal developing. Chicken embryo is a unique object for developmental studies that allows in vivo manipulations not always possible for mammalian embryos. Studies of synucleins expression in this model system could shed light on their functions in the developing nervous system. We cloned three chicken synucleins from the embryonic neural cDNA libraries and studied their expression in normal chicken embryonic tissues by Northern and in situ hybridization with specific probes. Our results demonstrate that primary structures and expression patterns of synucleins are similar in birds and mammals, suggesting that conserved function of synucleins is important for embryonic development of vertebrates.
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PMID:Chicken synucleins: cloning and expression in the developing embryo. 1109 Oct 93

Since recent reports have suggested that alpha-synuclein might play a role in neuronal plasticity, the main objective of this study was to determine the effects of alpha-synuclein on neuritic outgrowth. We stably transfected either human (h) alpha- or beta-synuclein cDNA in B103 rat neuronal cells. Expression of h(alpha)-synuclein resulted in reduced neurite extension and weak adhesion compared to vector-transfected and h(beta)-synuclein expressing cells. To investigate the potential pathways involved, we studied the effects of reagents known to modulate B103 proliferation and differentiation. Neither phorbol 12-myristate 13-acetate nor forskolin or antioxidants (catalase, superoxide dismutase, or vitamin E) were able to restore the reduced length of neurites in h(alpha)-synuclein-expressing cells. These results suggest that reduced neuritic activity in the h(alpha)-synuclein-expressing cells might be due, in part, to alterations in cell adhesion capacity. This might be attributed to alpha-synuclein affecting a signal transduction pathway distinct from protein kinase C and protein kinase A.
Mol Cell Neurosci 2001 Jan
PMID:Reduced neuritic outgrowth and cell adhesion in neuronal cells transfected with human alpha-synuclein. 1116 75


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