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)

Lewy bodies are intracellular fibrillar inclusions composed of alpha-synuclein. They constitute the pathological hallmark of Parkinson's disease, dementia with Lewy bodies, and other neurodegenerative diseases. Although the majority of Lewy bodies are stained for ubiquitin by immunohistochemistry, the substrate for this modification is poorly understood. Insoluble, urea-soluble alpha-synuclein was separated from soluble fractions and subjected to two-dimensional gel electrophoresis to further characterize pathogenic alpha-synuclein species from disease brains. By using this approach, we found that in sporadic Lewy body diseases a highly modified, disease-associated 22-24-kDa alpha-synuclein species is ubiquitinated. Conjugation of one, two, and, to a lesser extent, three ubiquitins was detected. This 22-24-kDa alpha-synuclein species represents partly phosphorylated protein. Furthermore, no generalized impairment of the proteolytic activity of the proteasome was detected in brain regions with Lewy body pathology. Because unmodified alpha-synuclein is degraded by the proteasome in a ubiquitin-independent manner, these data suggest that accumulation of modified 22-24-kDa alpha-synuclein is a disease-specific event which may overwhelm the proteolytic system, leading to aberrant ubiquitination. Accordingly, carboxyl-terminal-truncated alpha-synuclein, presumably the result of aberrant proteolysis, is found only in association with alpha-synuclein aggregates.
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PMID:Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. 1292 79

Mutations of parkin, a protein-ubiquitin isopeptide ligase (E3), appear to be the most frequent cause of familial Parkinson's disease (PD). Our previous studies have demonstrated that parkin binds strongly to alpha/beta tubulin heterodimers and microtubules. Here we show that the strong binding between parkin and tubulin, as well as that between parkin and microtubules, was mediated by three independent domains: linker, RING1, and RING2. These redundant strong interactions made it virtually impossible to separate parkin from microtubules by high concentrations of salt (3.8 m) or urea (0.5 m). Parkin co-purified with tubulin and was found in highly purified tubulin preparation. Expression of either full-length parkin or any of its three microtubule-binding domains significantly attenuated colchicine-induced microtubule depolymerization. The abilities of parkin to bind to and stabilize microtubules were not affected by PD-linked mutations that abrogate its E3 ligase activity. Thus, the tubulin/microtubule-binding activity of parkin and its E3 ligase activity are independent. The strong binding between parkin and tubulin/microtubules through three redundant interaction domains may not only stabilize microtubules but also guarantee the anchorage of this E3 ligase on microtubules. Because many misfolded proteins are transported on microtubules, the localization of parkin on microtubules may provide an important environment for its E3 ligase activity toward misfolded substrates.
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PMID:Parkin stabilizes microtubules through strong binding mediated by three independent domains. 1573 90

Aquaporins are a family of water channels found in animals, plants, and microorganisms. A subfamily of aquaporins, the aquaglyceroporins, are permeable for water as well as certain solutes such as glycerol, lactate, and urea. Here we show that the brain contains two isoforms of AQP9--an aquaglyceroporin with a particularly broad substrate specificity--and that the more prevalent of these isoforms is expressed in brain mitochondria. The mitochondrial AQP9 isoform is detected as an approximately 25 kDa band in immunoblots. This isoform is likely to correspond to a new AQP9 mRNA that is obtained by alternative splicing and has a shorter ORF than the liver isoform. Subfractionation experiments and high-resolution immunogold analyses revealed that this novel AQP9 isoform is enriched in mitochondrial inner membranes. AQP9 immunopositive mitochondria occurred in astrocytes throughout the brain and in a subpopulation of neurons in the substantia nigra, ventral tegmental area, and arcuate nucleus. In the latter structures, the AQP9 immunopositive mitochondria were located in neurons that were also immunopositive for tyrosine hydroxylase, as demonstrated by double labeling immunogold electron microscopy. Our findings suggest that mitochondrial AQP9 is a hallmark of astrocytes and midbrain dopaminergic neurons. In physiological conditions, the flux of lactate and other metabolites through AQP9 may confer an advantage by allowing the mitochondria to adjust to the metabolic status of the extramitochondrial cytoplasm. We hypothesize that the complement of mitochondrial AQP9 in dopaminergic neurons may relate to the vulnerability of these neurons in Parkinson's disease.
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PMID:Brain mitochondria contain aquaporin water channels: evidence for the expression of a short AQP9 isoform in the inner mitochondrial membrane. 1612 13

As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (Abeta) peptides, such as Abeta1-42. Absolute Abeta1-42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based Abeta-sodium-dodecylsulphate-polyacrylamide-gel-electrophoresis with Western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide pattern of the carboxy-terminally truncated Abeta peptides 1-37, 1-38, 1-39 in addition to 1-40 and 1-42 in human CSF. We used the Abeta-SDS-PAGE/immunoblot to investigate the CSF of 23 patients with Alzheimer's disease, 21 with DLB, 21 with PDD and 23 non-demented disease controls (NDC) for disease-specific alterations of the Abeta peptide patterns in its absolute and relative quantities. The diagnostic groups were matched for age and severity of dementia. The present study is the first attempt to evaluate the meaning of Abeta peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases--Alzheimer's disease, DLB and PDD. The Abeta peptide patterns displayed disease-specific variations and the ratio of the differentially altered Abeta1-42 to the Abeta1-37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Abeta-like immunoreactivity was observed constantly in the CSF of all 88 investigated patients. The pronounced percentage increase of this peptide in DLB allowed a highly significant discrimination from PDD. Using a cut-off point of 0.954%, this marker yielded a diagnostic sensitivity and specificity of 81 and 71%, respectively. From several lines of indication, we consider this peptide to represent an oxidized alpha-helical form of Abeta1-40 (Abeta1-40*). The increased abundance of Abeta1-40* probably reflects a disease-specific alteration of the Abeta1-40 metabolism in DLB. We conclude that Abeta peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Abeta peptide patterns failed to fulfil the requirements for a sole biomarker, their combined evaluation with other biomarkers is promising in neurochemical dementia diagnosis. It is noteworthy that DLB and PDD exhibit distinct clinical temporal courses, despite their similar neuropathological appearance. Their distinct molecular phenotypes support the view of different pathophysiological pathways for each of these neurodegenerative diseases.
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PMID:CSF amyloid-beta-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia. 1660 Sep 85

To evaluate variations in amyloid beta (Abeta) peptide pattern in cerebrospinal fluid (CSF) in neurodegenerative disorders. A recently established quantitative urea-based Abeta-sodium-dodecylsulfate-polyacrylamide-gel-electrophoresis with western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide (Abeta1-37, 1-38, 1-39, 1-40, 1-42) pattern in CSF. We asked whether the variation might be useful to further elucidate the overlap between or distinctions among neurodegenerative diseases in Abeta-processing. We used the Abeta-SDS-PAGE/immunoblot to investigate CSF for disease-specific Abeta peptide patterns. CSF samples from 96 patients with mainly clinically diagnosed Alzheimer's disease (n = 15), progressive supranuclear palsy (n = 20), corticobasal degeneration (n = 12), Parkinson's disease (n = 11), multiple systems atrophy (n = 18), and dementia with Lewy-bodies (n = 20) were analysed as well a comparison group (n = 19). The Abeta peptide patterns varied between tauopathies and synucleinopathies and between all diseases and the comparison group, possibly due to the influence of tau and alpha-synuclein on Abeta-processing.
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PMID:Tauopathies and synucleinopathies: do cerebrospinal fluid beta-amyloid peptides reflect disease-specific pathogenesis? 1731 5

E3 ubiquitin ligases are essential enzymes in the ubiquitination pathway responsible for the recognition of specific E2 conjugating enzymes and for transferring ubiquitin to a substrate targeted for degradation. In autosomal recessive juvenile Parkinson's disease, an early onset form of Parkinson's disease, point mutations in the E3 ligase parkin are one of the most commonly observed traits. Parkin is a multidomain E3 ligase that contains an N-terminal ubiquitin-like domain that interacts with, and effects the ubiquitination of, substrates such as cyclin E, p38 and synphilin. In this work we have examined the folding and structure of the parkin ubiquitin-like domain (Ubld) and of the protein with two causative disease mutations (K48A and R42P). Parallel experiments with the protein ubiquitin were done in order to determine if the same mutations were detrimental to the ubiquitin structure and stability. Despite similar folds between the parkin Ubld and ubiquitin, urea unfolding experiments show that the parkin Ubld is surprisingly approximately 10.6 kJ/mol less stable than ubiquitin. The K48A mutation had little effect on the stability of the parkin Ubld or ubiquitin indicating that this mutation contributes to defective protein-protein interactions. In contrast, the single point mutation R42P in parkin's Ubld caused poor expression and degradation of the protein. To avoid these problems, a GB1-Ubld fusion protein was characterized by NMR spectroscopy to show that the R42P mutation causes the complete unfolding of the parkin Ubld. This observation provides a rationale for the more rapid degradation of parkin carrying the R42P mutation in vivo, and its inability to interact with some substrate proteins. Our work provides the first structural and folding insight into the effects of causative mutations within the ubiquitin-like domain in autosomal recessive juvenile Parkinson's disease.
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PMID:A disease state mutation unfolds the parkin ubiquitin-like domain. 1800 87

Alpha-synuclein (alpha-Syn) fibrils are the major component of Lewy bodies that are closely associated with the pathogenesis of Parkinson's disease, but the mechanism for the fibril assembly remains poorly understood. Here we report using a combination of peptide truncation and atomic force microscopy (AFM) to elucidate the self-assembly and morphology of the alpha-Syn fibrils. The results show that protease K significantly slims the fibrils from the mean height of approximately 6.6 to approximately 4.7 nm, whereas chaotropic denaturant urea completely breaks down the fibrils into small particles. The in situ enzymatic digestion also results in thinning of the fibrils, giving rise to some nicks on the fibrils. Moreover, N- or C-terminally truncated alpha-Syn fragments assemble into thinner filaments with the heights depending on the peptide lengths. A nine-residue peptide corresponding to the homologous GAV-motif sequence can form very thin (approximately 2.2 nm) but long (>1 microm) filaments. Thus, the central sequence of alpha-Syn forms a fibrillar core by cross-beta-structure that is flanked by two flexible termini, and the orientation of the fibril growth is perpendicular to the beta-sheet structures.
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PMID:Assembly of alpha-synuclein fibrils in nanoscale studied by peptide truncation and AFM. 1823 Mar 46

To investigate whether Helicobacter pylori (HP) infection affects the clinical response to levodopa and whether its eradication could improve motor fluctuation in patients with Parkinson's disease (PD). Using the [(13)C] urea breath test, we monitored HP infection in 65 patients with PD and motor fluctuations of the "wearing-off" or delayed "on" types, with or without dyskinesia. We compared the clinical features and response to L-dopa between HP noninfected (n = 30) and HP infected patients (n = 35) by reviewing home diaries kept for 72 hours. Among HP infected patients, we compared the differences in L-dopa "onset" time, "on-time" duration, and scores on the motor examination section of the Unified PD Rating Scale (UPDRS-III) during the medication "on" phase before and after HP eradication. There were no differences in the age, disease duration, Hoehn and Yahr stage, UPDRS-III score, L-dopa daily dose, and frequency of dyskinesia between HP noninfected and HP infected groups. However, L-dopa "onset" time was longer and "on-time" duration was shorter in HP infected patients than in HP noninfected patients (78.4 +/- 28.2 vs. 56.7 +/- 25.1 and 210.0 +/- 75.7 vs. 257.7 +/- 68.9 min, respectively, P < 0.05). HP eradication improved the delay L-dopa "onset" time and short "on-time" duration (to 58.1 +/- 25.6 and to 234.4 +/- 66.5 min, respectively, P < 0.05). These data demonstrated that HP infection could interfere with the absorption of L-dopa and provoke motor fluctuations. HP eradication can improve the motor fluctuations of HP infected patients with PD.
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PMID:Helicobacter pylori infection and motor fluctuations in patients with Parkinson's disease. 1864 91

A series of 3-phenyl/ethyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7-yl urea and thiourea derivatives were designed and synthesized. All the compounds have been evaluated for their antiparkinsonian activity in catalepsy induced by haloperidol in mice. A majority of the compounds exhibited significant antiparkinsonian activity after intraperitoneal administration. The most active compound carries methoxy group at 2-position of the phenyl ring. Some of the potent compounds were selected for biochemical estimations of malondialdehyde, glutathione, superoxide dismutase and glutathione peroxidase from brain homogenate to highlight the neuroprotective properties associated with them. The results obtained in the present study may lead to the development of a suitable approach to the treatment of Parkinson's disease and may be the starting point for the future drug design.
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PMID:Synthesis of some urea and thiourea derivatives of 3-phenyl/ethyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidine and their antagonistic effects on haloperidol-induced catalepsy and oxidative stress in mice. 1944 24

Fibrils of the intrinsically disordered protein alpha-synuclein are hallmarks of Parkinson's disease. The fluorescent dye thioflavin T is often used to characterize fibrillation, but this assay may not provide quantitative information about structure and mechanism. To gain such information, we incorporated the 19F-labeled amino acid, 3-fluorotyrosine, into recombinant human alpha-synuclein at its endogenous tyrosine residues. Tyrosine 39 is in the positively charged N-terminal region of this 140-residue protein. The other three tyrosines, 125, 133, and 136, are near the C-terminus. 19F nuclear magnetic resonance spectroscopy was used to study several properties of labeled alpha-synuclein, including its conformation, conformational changes induced by urea, spermine, and sodium dodecyl sulfate (SDS), its interaction with SDS micelles, and the kinetics of fibril formation. The results show that the tyrosines are in disordered regions but that there is some structure near position 39 that is disrupted by urea. SDS binding alters the conformation near position 39, but the C-terminal tyrosines are disordered under all conditions. The NMR data also indicate that SDS-micelle-bound alpha-synuclein and the free protein exchange on the 10 ms time scale. Studies of fibrillation show the utility of 19F-labeled NMR. The data indicate that fibrillation is not accompanied by the formation of large quantities of low molecular weight intermediates. Although dye binding and 19F NMR data show that 1 mM SDS and 1 mM spermine accelerate aggregation compared to buffer alone, only the NMR data indicate that the species formed in SDS are smaller than those formed in buffer or buffer plus spermine. We conclude that 19F NMR spectroscopy is useful for obtaining residue-level, quantitative information about the structure, binding, and aggregation of alpha-synuclein.
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PMID:19F NMR studies of alpha-synuclein conformation and fibrillation. 1965 84


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