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)

Non-enzymatic products of neuroamines and endogenous carbonyl compounds are apparent "normal" products in human metabolism, and their levels become increased during pathological conditions. DA condensation products--salsolinol, its O-methylated derivative, and methylated derivatives of 1-carboxyl-THP--are found normally in human urine, and the last TIQ is in human brain. Potential beta-carboline condensation products also occur in (aging) human lens tissue. Chronic drinking in alcoholics causes significant increases in urinary salsolinol and O-methyl-salsolinol, presumably due to the increased AcH which is made available. L-DOPA therapy (in Parkinson's disease) elevates urinary and tissue levels of the carboxylated THP derivatives, as well as of salsolinol and THP itself; hyperphenylalaninemia during PKU also increases tissue levels of a DA/phenylpyruvate-derived TIQ and an imine condensate of phenylethylamine and vitamin B6. These unusual products may interfere with neural dynamic processes, and produce cytotoxic metabolites.
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PMID:Neuroamine condensations in human subjects. 740 16

(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for aromatic amino acid hydroxylases, such as phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), tryptophan hydroxylase, and nitric oxide synthase, which catalyze physiologically important reactions in mammals. The biosynthesis and metabolism of BH4 is usually studied mostly in the liver and only slightly in the brain, as the BH4 level in the liver is relatively high because BH4 is required for the reaction of PAH. We found that GTP (guanosine triphosphate) cyclohydrolase I, an enzyme for the biosynthesis of BH4, is a causative gene for DOPA (3,4-dihydroxyphenylalanine)-responsive dystonia (also called Segawa's disease), and that partial deficiency of BH4 leads to the dysfunction of the nigrostriatal dopaminergic neurons without hyperphenylalaninemia. We analyzed BH4-deficient mice that were produced by disruption of a BH4-synthesizing gene by a gene-knockout technique. We found that the protein amount of TH was highly dependent on the amount of BH4, especially in nerve terminals. Our research suggests that BH4 metabolism in the brain should be different from that in the liver, and that altered metabolism of BH4 should lead to neuropsychiatric disorders including Parkinson's disease.
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PMID:Metabolism of tetrahydrobiopterin: its relevance in monoaminergic neurons and neurological disorders. 1910 67

In a recent GCH1 mutation screen, an 18-bp deletion was identified within the proximal promoter in two patients with early-onset Parkinson's disease. The mutation removes cAMP response element critical for adequate GTP cyclohydrolase I activity in selected cell types, including dopaminergic neurons, but its biological significance was unclear as it was also detected in one control individual. We present an 11-year-old boy with infantile-onset severe dystonic encephalopathy without hyperphenylalaninemia whom we found compound heterozygous for the same promoter GCH1 deletion and another common missense mutation associated with classical dopa-responsive dystonia. Extensive diagnostic work up excluded other causes of dystonia, and comprehensive mutation scan did not reveal any additional GCH1 sequence variations, supporting the association between the promoter deletion and disease phenotype.
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PMID:Severe dystonic encephalopathy without hyperphenylalaninemia associated with an 18-bp deletion within the proximal GCH1 promoter. 2084 87

Tetrahydrobiopterin (BH4) deficiency causes hyperphenylalaninemia and impaired synthesis of serotonin and dopamine, leading to brain degeneration and early death if left untreated. Replacement therapy with neurotransmitters precursors is the cornerstone of treatment, relying on 5-hydroxytryptophan and L-dopa administration. Effective restoration of dopaminergic activity is thickened, like in Parkinson's disease, by the pulsatile pharmacokinetic profile of L-dopa. Monitoring of L-dopa therapy in BH4 deficiency is generally based upon clinical observation and periodical measurement of homovanillic acid (HVA) concentration in the cerebrospinal fluid (CSF). According to the finding that dopamine is the natural inhibitor of prolactin (PRL) incretion, we introduced the use of peripheral PRL measurement as an index of dopaminergic homeostasis, so avoiding the need of repeated lumbar punctures in patients with BH4 deficiency. As a single PRL evaluation can be misleading, due to the dependency of PRL fluctuations on L-dopa administration schedule, here we show that a short PRL profile is suitable for monitoring these patients. Together with the assessment of patients' clinical symptoms, this standardized tool will ensure an objective non-invasive reference to the management of dopaminergic replacement therapy in BH4 deficiency, even in patients treated with dopamine agonists.
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PMID:Short prolactin profile for monitoring treatment in BH4 deficiency. 2570 72

Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified DNAJC12 homozygous null variants (c.187A>T;p.K63* and c.79-2A>G;p.V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild nonprogressive, motor symptoms, sustained benefit from small dose of levodopa, and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology, and substantia nigra depigmentation with moderate cell loss. DNAJC12 transcripts were reduced in both patients. Our results suggest that DNAJC12 mutations (absent in 500 early-onset patients with Parkinson's disease) rarely cause dopa-responsive nonprogressive parkinsonism in adulthood, but broaden the clinical spectrum of DNAJC12 deficiency. Ann Neurol 2017;82:640-646.
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PMID:DNAJC12 and dopa-responsive nonprogressive parkinsonism. 2889 70