Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Employing primary cultures of astrocytes which seem to constitute a valid model of their in vivo counterparts, it has been demonstrated that this cell type is likely to be of importance in terminating the transmitter activity of GABA. It has been shown that the transport carrier in astrocytes is stereospecific for the C-4 hydrogens of the GABA molecule and that its structural requirements are distinct from those exhibited by the neuronal GABA carrier. beta-Proline was a selective inhibitor of GABA transport in astrocytes, whereas R-trans-4-methyl-4-aminocrotonic acid and S-nipecotic acid seemed to be selective inhibitors of neuronal GABA transport, as studied using very thin slices ("prisms") of brain cortex. These findings may be important for studies on the relative significance of the two transport systems in GABA-mediated neurotransmission, and thus for future pharmacological manipulations of the GABA system. This may eventually be beneficial for the treatment of neurological disorders such as epilepsy, Huntington's chorea and Parkinson's disease in which the GABA system seems to be disturbed (34,60,62).
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PMID:Effects of GABA-analogues on the high-affinity uptake of GABA in astrocytes in primary cultures. 4 81

Chemical modification of PLG, comprising replacement of proline or/and leucine by unnatural amino acids led to analogs with high oral efficacy. The most active analog identified in the course of our works was 1-prolyl-2-phenyl-1-2-aminobutanoylglycinamide (Doreptide). Doreptide is presently further evaluated as a new drug for the treatment of Parkinson's disease.
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PMID:L-dopa potentiating analogs of Pro-Leu-Gly-NH2 with oral efficacy. 167 11

Concentrations of putative neuroactive substances glutamate, aspartate, gamma-aminobutyric acid, glycine, proline and ethanolamine were determined in ventricular cerebrospinal fluid collected in patients suffering from Parkinson's disease, pain syndromes or cerebellar tremor. Values are similar to those given in the literature for lumbar cerebrospinal fluid. A decrease in gamma-aminobutyric acid in Parkinson patients, as reported in lumbar cerebrospinal fluid, could not be observed. Further evidence for a rostro-caudal gradient for gamma-aminobutyric acid is supplied. New insights into pathophysiological mechanisms in any of the investigated syndromes may not be derived.
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PMID:Ventricular cerebrospinal fluid concentrations of putative amino acid transmitters in Parkinson's disease and other disorders. 289 52

The effect of the N-terminal tripeptide of insulin-like growth factor (IGF)-1, glycine-proline-glutamate (GPE), as a neuroprotective agent for nigro-striatal dopaminergic neurons was examined in the present study using a rat model of Parkinson's disease. A unilateral nigro-striatal lesion was induced in rats by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB). GPE (3 microgram) or its vehicle was administered intracerebroventricularly (i.c.v.) 2 h after the 6-OHDA lesion. Tyrosine-hydroxylase (TH) immunohistochemistry in the substantia nigra compacta (SNc) and the striatum were examined 2 weeks after the lesion. Following 6-OHDA injection, the number of TH immunopositive neurons in the ipsilateral SNc was reduced. The density of TH immunostaining was also reduced in the ipsilateral SNc and the striatum. Treatment with a single dose of GPE (n=9) significantly prevented the loss of TH immunopositive neurons (p<0. 001) and restored the TH immunoreactivity in both the SNc and the striatum compared with the vehicle control group (n=9, p<0.001). The results suggest that GPE showed promise as a potential treatment for Parkinson's disease.
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PMID:N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats. 1071 76

Linkage of alpha-synuclein (alpha-SN) mutations to familial Parkinson's disease (PD) and presence of alpha-SN as a major constituent of Lewy body in both sporadic and familial PD implicate alpha-SN abnormality in PD pathogenesis. Here we demonstrate that overexpression of wild-type or mutant alpha-SN does not cause any deleterious effect on the growth or continued propagation of transfected human cells, but overproduction of mutant alpha-SN heightens their sensitivity to menadione-induced oxidative injury. Such enhanced vulnerability is more pronounced in neuronal transfectants than in their nonneuronal counterparts and is associated with increased production of reactive oxygen species. The data suggest that mutated alpha-SN, especially with an alanine-to-proline substitution at residue 30, sensitizes neuronal cells to oxidative damage.
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PMID:Sensitization of neuronal cells to oxidative stress with mutated human alpha-synuclein. 1108 Feb 8

The casein milk proteins and the brain proteins alpha-synuclein and tau have been described as natively unfolded with random coil structures, which, in the case of alpha-synuclein and tau, have a propensity to form the fibrils found in a number of neurodegenerative diseases. New insight into the structures of these proteins has been provided by a Raman optical activity study, supplemented with differential scanning calorimetry, of bovine beta- and kappa-casein, recombinant human alpha-, beta- and gamma-synuclein, together with the A30P and A53T mutants of alpha-synuclein associated with familial cases of Parkinson's disease, and recombinant human tau 46 together with the tau 46 P301L mutant associated with inherited frontotemporal dementia. The Raman optical activity spectra of all these proteins are very similar, being dominated by a strong positive band centred at approximately 1318 cm(-1) that may be due to the poly(l-proline) II (PPII) helical conformation. There are no Raman optical activity bands characteristic of extended secondary structure, although some unassociated beta strand may be present. Differential scanning calorimetry revealed no thermal transitions for these proteins in the range 15-110 degrees C, suggesting that the structures are loose and noncooperative. As it is extended, flexible, lacks intrachain hydrogen bonds and is hydrated in aqueous solution, PPII helix may impart a rheomorphic (flowing shape) character to the structure of these proteins that could be essential for their native function but which may, in the case of alpha-synuclein and tau, result in a propensity for pathological fibril formation due to particular residue properties.
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PMID:A Raman optical activity study of rheomorphism in caseins, synucleins and tau. New insight into the structure and behaviour of natively unfolded proteins. 1178 8

alpha-Synuclein (alpha-Syn) is an abundant presynaptic protein of unknown function, which has been implicated in the pathogenesis of Parkinson's disease. Alpha-Syn has been suggested to play a role in lipid transport and synaptogenesis, and growing evidence suggests that alpha-Syn interactions with cellular membranes are physiologically important. In the current study, we demonstrate that the familial Parkinson's disease-linked A30P mutant alpha-Syn is defective in binding to phospholipid vesicles in vitro as determined by vesicle ultracentrifugation, circular dichroism spectroscopy, and low-angle X-ray diffraction. Interestingly, our data also suggest that alpha-Syn may bind to the lipid vesicles as a dimer, which suggest that this species could be a physiologically relevant and functional entity. In contrast, the naturally occurring murine A53T substitution, which is also linked to Parkinson's disease, displayed a normal membrane-binding activity that was comparable to wild-type alpha-Syn. A double mutant A53T/A30P alpha-Syn showed defective membrane binding similar to the A30P protein, indicating that the proline mutation is dominant in terms of impairing the membrane-binding activity. With these observations, we suggest that the A53T and A30P mutants may have different physiological consequences in vivo and could possibly contribute to early onset Parkinson's disease via unique mechanisms.
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PMID:Defective membrane interactions of familial Parkinson's disease mutant A30P alpha-synuclein. 1181 48

Parkinson's disease (PD) is clinically characterized by a resting tremor, bradykinesia, cogwheel phenomenon, rigidity, disorder of postural reflexes and especially changes in voice and speech. We studied 30 PD patients who were treated with dopamine and 20 normal subjects as the control group. The parameters of vocal fold edges, glottal closure, vertical levels of cords, amplitude of vibration, mucosal wave, vibratory behavior, phase symmetry, ventricular folds and movements, periodicity, arytenoids and thick mucous were evaluated by videolaryngostroboscopy. The Unified Parkinson's Disease Rating Scale was applied to the patient group. The voices of the patients were evaluated by the Dr.Speech-4 and Spectra-PRO computer programs. Maximum phonation time, fundamental frequency, amplitude and the harmonic-to-noise ratio were recorded and compared with those of the control group. The abnormal videolaryngostroboscopic findings were more frequent in the PD group (70% versus 45%; P<0.05). Voice analysis showed significant differences in the parameters such as maximum phonation time, maximum fundamental frequency, the frequency range and the harmonic-to-noise ratio. We thought that these methods and parameters yielded sufficient information for diagnosis and follow-up of vocal function in patients with PD.
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PMID:Voice analysis and videolaryngostroboscopy in patients with Parkinson's disease. 1211 74

The recent discovery that small molecule ligands for the peptidyl-prolyl isomerase (PPIase) FKBP12 possess powerful neuroprotective and neuroregenerative properties in vitro and in vivo suggests therapeutic utility for such compounds in neurodegenerative disease. The neurotrophic effects of these compounds are independent of the immunosuppressive pathways by which drugs such as FK506 and rapamycin operate. Previous work by ourselves and other groups exploring the structure-activity relationships (SAR) of small molecules that mimic only the FKBP binding domain portion of FK506 has focused on esters of proline and pipecolic acid. We have explored amide and thioester analogues of these earlier structures and found that they too are extremely potent in promoting recovery of lesioned dopaminergic pathways in a mouse model of Parkinson's disease. Several compounds were shown to be highly effective upon oral administration after lesioning of the dopaminergic pathway, providing further evidence of the potential clinical utility of a variety of structural classes of FKBP12 ligands.
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PMID:Synthesis of N-glyoxyl prolyl and pipecolyl amides and thioesters and evaluation of their in vitro and in vivo nerve regenerative effects. 1213 66

Mammalian homologues of the Drosophila canonical transient receptor potential (TRP) proteins have been implicated to function as plasma membrane Ca(2+) channels. This study examined the role of TRPC1 in human neuroblastoma (SH-SY5Y) cells. SH-SY5Y cells treated with an exogenous neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)) significantly decreased TRPC1 protein levels. Confocal microscopy on SH-SY5Y cells treatment with MPP(+) showed decreased plasma membrane staining of TRPC1. Importantly, overexpression of TRPC1 reduced neurotoxicity induced by MPP(+). MPP(+)-induced alpha-synuclein expression was also suppressed by TRPC1 overexpression. Protection of SH-SY5Y cells against MPP(+) was significantly decreased upon the overexpression of antisense TRPC1 cDNA construct or the addition of a nonspecific transient receptor potential channel blocker lanthanum. Activation of TRPC1 by thapsigargin or carbachol decreased MPP(+) neurotoxicity, which was partially dependent on external Ca(2+). Staining of SH-SY5Y cells with an apoptotic marker (YO-PRO-1) showed that TRPC1 protects SH-SY5Y neuronal cells against apoptosis. Further, TRPC1 overexpression inhibited cytochrome c release and decreased Bax and Apaf-1 protein levels. Interpretation of the above data suggests that reduction in the cell surface expression of TRPC1 following MPP(+) treatment may be involved in dopaminergic neurodegeneration. Furthermore, TRPC1 may inhibit degenerative apoptotic signaling to provide neuroprotection against Parkinson's disease-inducing agents.
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PMID:TRPC1-mediated inhibition of 1-methyl-4-phenylpyridinium ion neurotoxicity in human SH-SY5Y neuroblastoma cells. 1554 11


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