Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The involvement of alpha-synuclein in neurodegenerative diseases was first suspected after the isolation of an alpha-synuclein fragment (NAC) from amyloid plaques in Alzheimer's disease (AD). Later, two different alpha-synuclein mutations were shown to be associated with autosomal-dominant Parkinson's disease (PD), but only in a small number of families. However, the discovery that alpha-synuclein is a major component of Lewy bodies and Lewy neurites, the pathological hallmarks of PD, confirmed its role in PD pathogenesis. Pathological aggregation of the protein might be responsible for neurodegeneration. In addition, soluble oligomers of alpha-synuclein might be even more toxic than the insoluble fibrils found in Lewy bodies. Multiple factors have been shown to accelerate alpha-synuclein aggregation in vitro. Therapeutic strategies aimed to prevent this aggregation are therefore envisaged. Although little has been learned about its normal function, alpha-synuclein appears to interact with a variety of proteins and membrane phospholipids, and may therefore participate in a number of signaling pathways. In particular, it may play a role in regulating cell differentiation, synaptic plasticity, cell survival, and dopaminergic neurotransmission. Thus, pathological mechanisms based on disrupted normal function are also possible.
Cell Mol Life Sci 2000 Dec
PMID:Alpha-synuclein and Parkinson's disease. 1121 16

Parkinson's disease (PD) is a common progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. Although mutations in alpha-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic neural cell death occurs remains unknown. Proteins encoded by two other genes in which mutations cause familial PD, parkin and UCH-L1, are involved in regulation of the ubiquitin-proteasome pathway, suggesting that dysregulation of the ubiquitin-proteasome pathway is involved in the mechanism by which these mutations cause PD. We established inducible PC12 cell lines in which wild-type or mutant alpha-synuclein can be de-repressed by removing doxycycline. Differentiated PC12 cell lines expressing mutant alpha-synuclein showed decreased activity of proteasomes without direct toxicity. Cells expressing mutant alpha-synuclein showed increased sensitivity to apoptotic cell death when treated with sub-toxic concentrations of an exogenous proteasome inhibitor. Apoptosis was accompanied by mitochondrial depolarization and elevation of caspase-3 and -9, and was blocked by cyclosporin A. These data suggest that expression of mutant alpha-synuclein results in sensitivity to impairment of proteasome activity, leading to mitochondrial abnormalities and neuronal cell death.
Hum Mol Genet 2001 Apr 15
PMID:Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. 1130 65

The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human 293 Tet-Off cells. These structures contain aggregated, ubiquitinated huntingtin exon 1 protein with a characteristic fibrillar morphology. Inclusion bodies with truncated huntingtin protein are formed at centrosomes and are surrounded by vimentin filaments. Inhibition of proteasome activity resulted in a twofold increase in the amount of ubiquitinated, SDS-resistant aggregates, indicating that inclusion bodies accumulate when the capacity of the ubiquitin-proteasome system to degrade aggregation-prone huntingtin protein is exhausted. Immunofluorescence and electron microscopy with immunogold labeling revealed that the 20S, 19S, and 11S subunits of the 26S proteasome, the molecular chaperones BiP/GRP78, Hsp70, and Hsp40, as well as the RNA-binding protein TIA-1, the potential chaperone 14-3-3, and alpha-synuclein colocalize with the perinuclear inclusions. In 293 Tet-Off cells, inclusion body formation also resulted in cell toxicity and dramatic ultrastructural changes such as indentations and disruption of the nuclear envelope. Concentration of mitochondria around the inclusions and cytoplasmic vacuolation were also observed. Together these findings support the hypothesis that the ATP-dependent ubiquitin-proteasome system is a potential target for therapeutic interventions in glutamine repeat disorders.
Mol Biol Cell 2001 May
PMID:Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. 1135 30

Alpha-synuclein is mutated in some hereditary cases of Parkinson's disease and the protein precipitates in Lewy bodies, the pathological hallmark of both Parkinson's disease and Lewy body disease. Transgenic mice overexpressing human wild-type alpha-synuclein develop alpha-synuclein-immunoreactive inclusions in brain regions typically affected with Lewy body disease. We used in situ hybridization to characterize alpha-synuclein expression and examine mRNA levels in patients affected with Lewy body disease and controls. Substantia nigra was avoided because of the extensive neuronal loss and cingulate gyrus was chosen as it is one of the diagnostic regions in Lewy body disease where Lewy bodies most frequently are demonstrated. beta-tubulin was used to control for neuronal degeneration. The alpha-synuclein probe showed intense labeling of pyramidal cells in lamina III and V in both patients and controls. We found no difference in alpha-synuclein mRNA levels and beta-tubulin mRNA was not significantly altered (P=0.06) in patient brains. There was no difference in the ratio of alpha-synuclein and beta-tubulin mRNA levels between patients and controls. Further, we found no relationship between alpha-synuclein mRNA levels and Lewy bodies. Great variability in alpha-synuclein mRNA levels among patients indicates that Lewy body disease may be a heterogeneous disorder with regard to alpha-synuclein involvement.
Brain Res Mol Brain Res 2001 Aug 15
PMID:Expression of alpha-synuclein in the human brain: relation to Lewy body disease. 1148 42

We report haplotype analysis of the alpha-synuclein gene in Parkinson's disease (PD), extending earlier reports of an association with a polymorphism within the gene promoter. This analysis showed significant differences in haplotypes between PD cases and controls. Our analyses demonstrate that genetic variability in the alpha-synuclein gene is a risk factor for the development of PD. These genetic findings are analogous to the tau haplotype over-represented in progressive supranuclear palsy and further extend the similarity in the etiologies and pathogeneses of the synucleinopathies and tauopathies.
Hum Mol Genet 2001 Aug 15
PMID:alpha-Synuclein gene haplotypes are associated with Parkinson's disease. 1153 93

alpha-Synuclein is a highly conserved presynaptic protein with probable roles in normal synaptic development and plasticity as well as neurodegenerative disease, although its molecular function is not yet clear. To identify potential protein binding partners of alpha-synuclein, we performed co-immunoprecipitations using a monoclonal antibody (H3C) against its C-terminus. More than 20 detectable proteins were specifically co-immunoprecipitated from zebra finch and mouse forebrain extracts. One of these, with relative mobility of 55 kDa, was identified through microsequencing as a mixture of alpha- and beta-tubulin. Tubulin was specifically recovered from a mouse forebrain cytosolic extract by a GST/alpha-synuclein fusion protein immobilized on glutathione-Sepharose beads. In the converse experiment, alpha-synuclein bound to a column prepared from purified bovine brain tubulin immobilized upon CNBr-Sepharose. alpha-Synuclein does not appear to bind assembled microtubules, however, as alpha-synuclein did not pellet with polymerized microtubules in a standard assay for microtubule-associated proteins. Likewise, when a fusion construct of alpha-synuclein and green fluorescent protein (GFP) was expressed in African green monkey kidney epithelial (CV-1) cells, the fusion protein did not colocalize with endogenous microtubules. We conclude that alpha-synuclein may interact specifically with heterodimeric tubulin, but not microtubules, in the neuronal cytosol.
Brain Res Mol Brain Res 2001 Nov 01
PMID:Protein-protein interactions of alpha-synuclein in brain homogenates and transfected cells. 1168 85

Multiple system atrophy is an adult onset neurodegenerative disease, featuring parkinsonism, ataxia, and autonomic failure, in any combination. The condition is relentlessly progressive and responds poorly to treatment. Death occurs on average six to seven years after the onset of symptoms. No familial cases of multiple system atrophy have been reported, and no environmental factors have been robustly implicated as aetiological factors. However, analytical epidemiological studies are hampered because the condition is relatively rare. The discovery of the glial cytoplasmic inclusion (GCI) in 1989 helped to define multiple system atrophy as a clinicopathological entity, and drew attention to the prominent, if not primary, role played by the oligodendrocyte in the pathogenesis of the condition. Subsequently, GCIs were shown to be positive for alpha-synuclein, with immunostaining for this protein indicating that white matter pathology was more widespread than had previously been recognised. The presence of alpha-synuclein in GCIs provides a link with Parkinson's disease, dementia with Lewy bodies, and neurodegeneration with brain iron accumulation, type 1 (or Hallervorden-Spatz syndrome), in which alpha-synuclein is also found within Lewy bodies. This has led to the term "synucleinopathy" to embrace this group of conditions. The GCIs of multiple system atrophy contain a range of other cytoskeletal proteins. It is unknown how fibrillogenesis occurs, and whether there is primary oligodendrocytic dysfunction, which then disrupts the neurone/axon as a consequence of the glial pathology, or whether the oligodendrocytic changes merely represent an epiphenomenon. Further research into this devastating condition is urgently needed to improve our understanding of the pathogenesis, and also to produce new treatment approaches.
Mol Pathol 2001 Dec
PMID:Multiple system atrophy: cellular and molecular pathology. 1172 18

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.
Brain Res Mol Brain Res 2001 Dec 16
PMID:Transfected synphilin-1 forms cytoplasmic inclusions in HEK293 cells. 1174 67

Mutations in the alpha-synuclein gene (SNCA) have been implicated in familial Parkinson's disease (PD) while certain polymorphic alleles at a microsatellite repeat, NACP-Rep1, located approximately 10 kb upstream of the gene, have been associated with sporadic PD. In order to study the regulation of the human alpha-synuclein gene, we performed a deletion analysis of 10.7 kb upstream of the translational start site, using the luciferase reporter assay in 293T cells and the neuroblastoma cell line SH-SY5Y. The shortest fragment, 400 bp upstream of the transcriptional start site, was sufficient for transcription in both cell lines. The other constructs led to variable expression levels, with some showing maximum expression and others showing nearly complete extinction of expression. An 880 bp fragment located approximately 10 kb upstream of the gene and containing the NACP-Rep1 polymorphism, was shown to be necessary for normal expression. Additional analysis of the NACP-Rep1 locus and surrounding DNA suggested that two domains flanking the repeat interact to enhance expression while the repeat acts as a negative modulator. Next, we measured the activity of the entire 10.7 kb upstream region in the luciferase reporter assay when each of our different NACP-Rep1 alleles were present. The expression levels varied very significantly among the different alleles over a 3-fold range in the SH-SY5Y cells but showed little or no significant variation in the 293T cells. Given that even small changes in alpha-synuclein expression may, over many decades, predispose to PD, the association of different NACP-Rep1 alleles with PD may be a consequence of polymorphic differences in transcriptional regulation of alpha-synuclein expression resulting from different NACP-Rep1 alleles.
Hum Mol Genet 2001 Dec 15
PMID:Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. 1175 92

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders in humans. They are characterized by insoluble protein deposits; beta-amyloid plaques and tau-containing neurofibrillary lesions in AD, and alpha-synuclein-containing Lewy bodies in PD. As a significant percentage of patients have clinical and pathological features of both diseases, the patho-cascades of the two diseases might overlap. For the first time, new animal models that express multiple transgenes provide the tools to dissect the pathogenic pathways and to differentiate between additive and synergistic effects.
Trends Mol Med 2002 Jan
PMID:Alzheimer's and Parkinson's disease--overlapping or synergistic pathologies? 1179 55


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