dopamine biosynthesis
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Author(s):  
Anna Kuukasjärvi ◽  
Juan C. Landoni ◽  
Jyrki Kaukonen ◽  
Mika Juhakoski ◽  
Mari Auranen ◽  
...  

AbstractThe aetiology of dystonia disorders is complex, and next-generation sequencing has become a useful tool in elucidating the variable genetic background of these diseases. Here we report a deleterious heterozygous truncating variant in the inosine monophosphate dehydrogenase gene (IMPDH2) by whole-exome sequencing, co-segregating with a dominantly inherited dystonia-tremor disease in a large Finnish family. We show that the defect results in degradation of the gene product, causing IMPDH2 deficiency in patient cells. IMPDH2 is the first and rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders. We report IMPDH2 as a new gene to the dystonia disease entity. The evidence underlines the important link between guanine metabolism, dopamine biosynthesis and dystonia.


2021 ◽  
pp. 1-16
Author(s):  
Mehdi Mohammadi Azni ◽  
Hossein Moradi ◽  
Kamran Ghasemi ◽  
Pourya Biparva

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1291-1291
Author(s):  
Rosa Keller ◽  
Laura Beaver ◽  
Patrick Reardon ◽  
Jan Stevens ◽  
Norman Hord

Abstract Objectives Dietary nitrate supplementation shows protective effects against cardio-metabolic disease, decreases pulmonary oxygen uptake, and improves exercise performance in animal models and humans. However, the biological effect of nitrate on energy metabolism in the liver is not well understood. The objective of this study was to elucidate changes in liver metabolism associated with nitrate treatment and exercise. Methods Fish were exposed to sodium nitrate (606.9 mg/L), or control water, for 21 days and analyzed at intervals during a strenuous exercise test. We utilized untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to determine the effect of nitrate treatment and exercise on the liver metabolome. We measured gene expression of 31 genes linked to energy metabolism and redox signaling. Results In the absence of exercise, nitrate treatment upregulated expression of genes central to nutrient sensing (pgc1a and sirt3), protein synthesis (mtor) and purine metabolism (pnp5a and ampd1) and downregulated expression of genes involved in mitochondrial fat oxidation (acaca, cpt2 and hadh). Upregulation of these genes was associated with an increased abundance of metabolites involved in endogenous nitric oxide metabolism, dopamine biosynthesis, branched chain amino acid metabolism, and lipid metabolism in nitrate-treated livers at rest, compared to rested controls. As expected, the availability of these metabolites was diminished in nitrate-treated livers relative to rested controls. We found no significant change in gene of metabolites directly linked to glycolysis. Conclusions The main novel finding of this study was that sub-chronic nitrate treatment altered dopamine biosynthesis, protein synthesis and lipid metabolism in zebrafish liver without exercise. This is significant because dietary nitrate is emerging as an interesting therapeutic modality for metabolic syndrome and non-alcoholic fatty liver disease by preventing lipid accumulation in the liver. Funding Sources Celia Strickland and G. Kenneth Austin III Endowment and National Institutes of Health.


2021 ◽  
Vol 14 (5) ◽  
pp. e240067
Author(s):  
Kazuyuki Togo ◽  
Toshiya Ishihara ◽  
Kenji Yamamoto ◽  
Hideyuki Sawada

Pterin species participate in dopamine biosynthesis, and abnormal pteridine metabolism contributes to reduced dopamine. GTP cyclohydrolase 1 (GCH-1) deficiency, which triggers pteridine hypometabolism and normally develops in childhood, can mediate an adult-onset decrease in levodopa production and dopa-responsive dystonia (DRD), with normal dopamine transporter single-photon emission computed tomography (DAT-SPECT). A recent study described normal DAT-SPECT in adult-onset cases with GCH-1 mutations, clinically diagnosed with Parkinson’s disease, which raises the possibility that the abnormal metabolism of pteridine may be a differential diagnosis for adult-onset parkinsonism. We report an older patient with levodopa-responsive parkinsonism with normal DAT-SPECT, or scans without evidence of dopamine deficit (SWEDD), whose biochemical analysis showed pterin hypometabolism, which occurs in GCH-1-deficient DRD. Surprisingly, this patient presented no dystonia or GCH-1 gene mutation or deletion. This case suggests that low pterin metabolism should be considered in older-onset levodopa-responsive parkinsonism with normal DAT-SPECT, even without GCH-1 mutations or deletions.


2021 ◽  
Author(s):  
Kai Liu ◽  
Longyu Yuan ◽  
Lei Yue ◽  
Weiwen Chen ◽  
Kui Kang ◽  
...  

Abstract Insect fecundity is a quantitative phenotype strongly affected by genotypes and the environment. However, the interaction between genotypes and the environment factors in modulating the insect fecundity remains largely unknown. In this study, we investigated the density-dependent population dynamics in the brown planthopper (BPH), Nilaparvata lugens , by using two populations respectively carrying homozygous high-fecundity (HFG) and low-fecundity (LFG) genotypes. Under low population densities, the fecundity and population growth rate of the two genotypes showed increasing trends across generations, while the trends between HFG and LFG under high population densities were opposite. RNA-seq was applied to unveil the key factors for these density-dependent progenitive phenotypes. Combined with the temporal analysis and weighted gene co-expression network analysis, we identified two gene modules that simultaneously enriched in four pathways related to the neural system. Among these pathways, the gene Nlpale encoding a tyrosine hydroxylase was identified as the key gene. The RNA interference of this gene and manipulation of its downstream product dopamine could significantly impact the basic and density-dependent progenitive phenotypes of BPH. This study shows that the dopamine biosynthesis is the key regulatory factor for the determination of fecundity in response to density changes in different genotypes of BPH , which gives an insight into the interaction of a typical environmental factor and insect genotype during the process of population regulation.


2020 ◽  
Vol 21 (11) ◽  
pp. 3779 ◽  
Author(s):  
Ichiro Kawahata ◽  
Kohji Fukunaga

Nigrostriatal dopaminergic systems govern physiological functions related to locomotion, and their dysfunction leads to movement disorders, such as Parkinson’s disease and dopa-responsive dystonia (Segawa disease). Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine biosynthesis, is reduced in Parkinson’s disease and dopa-responsive dystonia; however, the mechanism of TH depletion in these disorders remains unclear. In this article, we review the molecular mechanism underlying the neurodegeneration process in dopamine-containing neurons and focus on the novel degradation pathway of TH through the ubiquitin-proteasome system to advance our understanding of the etiology of Parkinson’s disease and dopa-responsive dystonia. We also introduce the relation of α-synuclein propagation with the loss of TH protein in Parkinson’s disease as well as anticipate therapeutic targets and early diagnosis of these diseases.


2020 ◽  
Author(s):  
Aditi Verma ◽  
Priya Suresh ◽  
Barathan Gnanabharathi ◽  
Etienne C. Hirsch ◽  
Vijayalakshmi Ravindranath

AbstractWe performed transcriptome analysis using RNA sequencing on substantia nigra pars compacta (SNpc) from mice after acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and Parkinson’s disease (PD) patients. Acute and chronic exposure to MPTP resulted in decreased expression of genes involved in sodium channel regulation. However, upregulation of pro-inflammatory pathways was seen after single dose but not after chronic MPTP treatment. Dopamine biosynthesis and synaptic vesicle recycling pathways were downregulated in PD patients and after chronic MPTP treatment in mice. Genes essential for midbrain development and determination of dopaminergic phenotype such as, LMX1B, FOXA1, RSPO2, KLHL1, EBF3, PITX3, RGS4, ALDH1A1, RET, FOXA2, EN1, DLK1, GFRA1, LMX1A, NR4A2, GAP43, SNCA, PBX1, and GRB10 were downregulated in human PD and overexpression of LMX1B rescued MPP+ induced death in SH-SY5Y neurons. Downregulation of gene ensemble involved in development and differentiation of dopaminergic neurons indicate their critical involvement in pathogenesis and progression of human PD.


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