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)

The incorporation of labelled carbon from glucose U-14C into CSF amino acids was investigated in three patients with Parkinson's disease and in three control persons with comparable age and physical stature. Comparing the specific radioactivities of serum and CSF one can postulate that the labelled amino acids found in the CSF are synthesized mainly by brain tissue. The resorption of glucose into the CNS and therefore the synthesis of amino acids from glucose was more rapid in controls; labelled alanine and glutamine appeared later in the CSF of the patients. As expected, in the controls the specific radioactivity of glutamic acid was found to be higher than that of glutamine, in patients the labelling of glutamine was higher as was that of serine, glycine, aspartic acid and asparagine. From our knowledge concerning the compartmentation of the metabolism of glutamate, we assume that in Parkinsonism the metabolic activity of neurons is reduced but that of astroglia is enhanced.
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PMID:[Biosynthesis of amino acids from glucose in the central nervous system in the Parkinson syndrome]. 665 3

Accumulation of various mutations in the mitochondrial genome is proposed as an important contributor to aging and degenerative diseases. Extensive fragmentation of mtDNA was detected in association with increased 8-hydroxydeoxyguanosine content in the heart mitochondrial DNA (mtDNA) from a patient with premature aging and mitochondrial cardiomyopathy, who carried a mutation within the mitochondrial tRNA(Asp) gene. This result suggests that damage to mtDNA by hydroxyl radical and accumulation of deleted mtDNA can be accelerated by a specific mitochondrial genotype. Similarly, extensive fragmentation of mtDNA was also detected in cultured cells exposed to a high oxygen concentration atmosphere, implying that mtDNA is vulnerable to reactive oxygen species. To clarify the role of point mutations accumulated in mtDNA, we examined the sequence heterogeneity of mtDNA in the skeletal muscle of a MELAS patient who carried a mutation within the mitochondrial tRNA(leu)(UUR) gene. The analysis revealed that the frequency of mutant clones in the MELAS muscle was significantly higher than those in an age-matched control muscle and a control placenta. Some of these nucleotide substitutions were missense and nonsense mutations, which potentially have deleterious effects on the mitochondrial function. The frequency of nucleotide substitutions in the striatum of three patients with Parkinson's disease was also significantly higher than that in control tissues. We also observed increased protein modification by 4-hydroxy-2-nonenal, a lipid peroxidation by-product, in Parkinson's disease. These results suggests that a vicious cycle contributes to the progression of degenerative process. In this cycle, first a primary mitochondrial mutation(s) induces a mitochondrial respiratory defect, which increases the leakage of reactive oxygen species (ROS) from the respiratory chain. Then the ROS would trigger accumulation of secondary mtDNA mutations in postmitotic cells, leading to further aggravation of mitochondrial respiratory defects and increased production of ROS and lipid peroxides from mitochondria, and thus resulting in degeneration of cellular components.
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PMID:Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases. 868 11

PDZ domains are multifunctional protein-interaction motifs that often bind to the C-terminus of protein targets. Nitric oxide (NO), an endogenous signaling molecule, plays critical roles in nervous, immune, and cardiovascular function. Although there are numerous physiological functions for neuron-derived NO, produced primarily by the neuronal NO synthase (nNOS), excess nNOS activity mediates brain injury in cerebral ischemia and in animal models of Parkinson's disease. Subcellular localization of nNOS activity must therefore be tightly regulated. To determine ligands for the PDZ domain of nNOS, we screened 13 billion distinct peptides and found that the nNOS-PDZ domain binds tightly to peptides ending Asp-X-Val. This differs from the only known (Thr/Ser)-X-Val consensus that interacts with PDZ domains from PSD-95. Preference for Asp at the -2 peptide position is mediated by Tyr-77 of nNOS. A Y77D78 to H77E78 substitution changes the binding specificity from Asp-X-Val to Thr-X-Val. Guided by the Asp-X-Val consensus, candidate nNOS interacting proteins have been identified including glutamate and melatonin receptors. Our results demonstrate that PDZ domains have distinct peptide binding specificity.
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PMID:PDZ domain of neuronal nitric oxide synthase recognizes novel C-terminal peptide sequences. 909 34

Mutations in mitochondrially encoded tRNA genes have been described in a variety of neurological disorders. One such mutation, the A to G transition at nucleotide position 4336 of the mitochondrial tRNA(Gln) gene, has been associated with both Alzheimer and Parkinson disease. We have now performed a complete sequence analysis of all 22 mitochondrially encoded tRNA genes in 20 cases of histologically proven idiopathic Parkinson disease. Genomic DNA extracted from the substantia nigra of frozen or formalin-fixed and paraffin-embedded brains was used for amplification by polymerase chain reaction followed by automated sequencing. Two new homoplasmic point mutations were detected in the genes for tRNA(Thr) (15950 G/A) and tRNA(Pro) (15965 T/C) in 1 patient each. Restriction enzyme digestion revealed absence of the 15950 G/A mutation in 96 controls and in 40 cases of neuropathologically confirmed Alzheimer disease. The 15965 T/C mutation was shown to be absent from 100 control subjects and 47 Alzheimer cases. In addition to the two novel mutations, six known sequence variants were detected in a total of 6 different patients in the genes for tRNA(Asp) (G7521A, 1), tRNA(Arg) (T10463C, 1), tRNA(LeuCUN) (A12308G, 2), and tRNA(Thr) (A15924G, 1; G15928A, 2), including 1 patient carrying the tRNA(Gln) (A4336G) mutation. The G15950A transition affects position 70 of the aminoacyl acceptor stem of tRNA(Thr), which has been implicated as a recognition element for threonyl-tRNA synthetase and, at least in some tRNAs, in the processing of primary mitochondrial transcripts. The T15965C point mutation in the mitochondrial tRNA(Pro) gene alters position 64 of the TpsiC stem. The corresponding nucleotide in bacterial aminoacyl-tRNAs is involved in the interaction with elongation factor Tu. Thus, the two novel mutations are likely to be of functional relevance and could contribute to dopaminergic nerve cell death in affected individuals.
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PMID:Two novel point mutations of mitochondrial tRNA genes in histologically confirmed Parkinson disease. 1036 89

Altered expression of CYP2D6 (debrisoquine hydroxylase), resulting from genetic polymorphism at the CYP2D6 gene locus, is responsible for pronounced interindividual variation in the metabolism of many clinically important drugs. Although CYP2D6 substrates are structurally diverse, most are small molecules that interact with the protein via an electrostatic interaction between a basic nitrogen which is common to the majority of CYP2D6 substrates and an aspartic acid residue in the active site of the protein. As CYP2D6 substrates have a wide range of pharmacological functions, any variation in CYP2D6 expression can have profound clinical consequences. CYP2D6 activity can be determined both by phenotyping methods with a variety of probe drugs and by genotyping methods where PCR-based techniques are used to investigate the inheritance of individual CYP2D6 alleles. Allele frequencies have been shown to vary widely between populations of different racial origin. For example, the PM genotype is particularly rare in Orientals. The inheritance of certain CYP2D6 allelic variants has been associated with altered susceptibility to Parkinson's disease and several types of cancer.
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PMID:Cytochrome P450 CYP2D6. 1049 60

Recent works suggest that alpha-synuclein could play a central role in Parkinson's disease (PD). Thus, two mutations were reported to be associated with rare autosomal dominant forms of the disease. We examined whether alpha-synuclein could modulate the caspase-mediated response and vulnerability of murine neurons in response to various apoptotic stimuli. We established TSM1 neuronal cell lines overexpressing wild-type (wt) alpha-synuclein or the PD-related Ala-53 --> Thr mutant alpha-synuclein. Under basal conditions, acetyl-Asp-Glu-Val-Asp-aldehyde-sensitive caspase activity appears significantly lower in wt alpha-synuclein-expressing cells than in neurons expressing the mutant. Interestingly, wt alpha-synuclein drastically reduces the caspase activation of TSM1 neurons upon three distinct apoptotic stimuli including staurosporine, etoposide, and ceramide C(2) when compared with mock-transfected cells. This inhibitory control of the caspase response triggered by apoptotic agents was abolished by the PD-related pathogenic mutation. Comparison of wild-type and mutated alpha-synuclein-expressing cells also indicates that the former exhibits much less vulnerability in response to staurosporine and etoposide as measured by the sodium 3'-[1-(phenylaminocarbonyl)-3, 4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonic acid assay. Altogether, our study indicates that wild-type alpha-synuclein exerts an antiapoptotic effect in neurons that appears to be abolished by the Parkinson's disease-related mutation, thereby suggesting a possible mechanism underlying both sporadic and familial forms of this neurodegenerative disease.
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PMID:Wild-type but not Parkinson's disease-related ala-53 --> Thr mutant alpha -synuclein protects neuronal cells from apoptotic stimuli. 1081 98

Despite the identification of several mutations in familial Parkinson's disease (PD), the underlying mechanisms of dopaminergic neuronal loss in idiopathic PD are still unknown. To study whether caspase-dependent apoptosis may play a role in the pathogenesis of PD, we examined 6-hydroxydopamine (6-OHDA) toxicity in dopaminergic SH-SY5Y cells and in embryonic dopaminergic mesencephalic cultures. 6-OHDA induced activation of caspases 3, 6 and 9, chromatin condensation and cell death in SH-SY5Y cells. The caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethylketone (zVAD-fmk) or adenovirally mediated ectopic expression of the X-chromosomal inhibitor of apoptosis protein (XIAP) blocked caspase activation and prevented death of SH-SY5Y cells. Similarly, zVAD-fmk provided protection from 6-OHDA-induced loss of tyrosine hydroxylase-positive neurones in mesencephalic cultures. In contrast, zVAD-fmk failed to protect mesencephalic dopaminergic neurones from 6-OHDA-induced loss of neurites and reduction of [(3)H]dopamine uptake. These data suggest that, although caspase inhibition provides protection from 6-OHDA-induced death of dopaminergic neurones, the neurones may remain functionally impaired.
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PMID:Rescue from death but not from functional impairment: caspase inhibition protects dopaminergic cells against 6-hydroxydopamine-induced apoptosis but not against the loss of their terminals. 1127 82

The parkin protein is important for the survival of the neurons that degenerate in Parkinson's disease as demonstrated by disease-causing lesions in the parkin gene. The Chinese hamster ovary and the SH-SY5Y cell line stably expressing recombinant human parkin combined with epitope-specific parkin antibodies were used to investigate the proteolytic processing of human parkin during apoptosis by immunoblotting. Parkin is cleaved during apoptosis induced by okadaic acid, staurosporine, and camptothecin, thereby generating a 38-kDa C-terminal fragment and a 12-kDa N-terminal fragment. The cleavage was not significantly affected by the disease-causing mutations K161N, G328E, T415N, and G430D and the polymorphism R366W. Parkin and its 38-kDa proteolytic fragment is preferentially associated with vesicles, thereby indicating that cleavage is a membrane-associated event. The proteolysis is sensitive to inhibitors of caspases. The cleavage site was mapped by site-directed mutagenesis of potential aspartic residues and revealed that mutation of Asp-126 alone abrogated the parkin cleavage. The tetrapeptide aldehyde LHTD-CHO, representing the amino acid sequence N-terminal to the putative cleavage site was an efficient inhibitor of parkin cleavage. This suggests that parkin function is compromised in neuropathological states associated with an increased caspase activation, thereby further adding to the cellular stress.
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PMID:Caspase-mediated parkin cleavage in apoptotic cell death. 1183 50

Parkinson's disease is characterized by a loss of dopaminergic nigrostriatal neurons. This neuronal loss is mimicked by the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). MPP+ toxicity is mediated through inhibition of mitochondrial complex I, decreasing ATP production, and upregulation of oxygen radicals. There is evidence that the cell death induced by MPP+ is apoptotic and that inhibition of caspases may be neuroprotective. In primary cultures of rat mesencephalic dopaminergic neurons, MPP+ treatment decreased the number of surviving dopaminergic neurons in the cultures and the ability of the neurons to take up [3H]dopamine ([3H]DA). Caspase inhibition using the broad-spectrum inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) spared MPP+-treated dopaminergic neurons and increased somatic size. There was a partial restoration of neurite length in zVAD-fmk-treated cultures, but little restoration of [3H]DA uptake. Peptide inhibitors of caspases 2, 3, and 9, but not of caspase 1, caused significant neuroprotection. Two novel caspase inhibitors were tested for neuroprotection, a broad spectrum inhibitor and a selective caspase 3 inhibitor; both inhibitors increased survival to >90% of control. No neuroprotection was observed with an inactive control compound. MPP+ treatment caused chromatin condensation in dopaminergic neurons and increased expression of activated caspase 3. Inhibition of caspases with either zVAD-fmk or a selective caspase 3 inhibitor decreased the number of apoptotic profiles, but not expression of the active caspase. We conclude that MPP+ toxicity in primary dopaminergic neurons involves activation of a pathway terminating in caspase 3 activation, but that other mechanisms may underlie the neurite loss.
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PMID:Caspase inhibitors attenuate 1-methyl-4-phenylpyridinium toxicity in primary cultures of mesencephalic dopaminergic neurons. 1192 29

Recently, it has been shown that rotenone, a specific inhibitor of mitochondrial complex I, is a useful tool in animal models of Parkinson's disease, but the mechanism of rotenone-induced neuronal death is not fully understood. In human neuroblastoma SH-SY5Y cells, rotenone induced the degradation of procaspases-12, -9 and -3, followed by cleavage of poly (adenosine diphosphate-ribose) polymerase, DNA fragmentation and cell death. Pretreatment with phorbol-12-myristate-13-acetate inhibited the rotenone-induced decrease in procaspases-9 and -3, but not that in procaspase-12. In contrast, benzyloxycarbonyl-Val-Ala-Asp(OCH(3))-CH(2)F inhibited the decrease in procaspase-12, but not those in procaspases-9 and -3 in this study. These results suggest that rotenone may induce activation of both mitochondria- and endoplasmic reticulum-dependent caspases in human SH-SY5Y cells.
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PMID:Possible involvement of both mitochondria- and endoplasmic reticulum-dependent caspase pathways in rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells. 1240 52


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