China
Africa
Explore chapters and articles related to this topic
Role of Tandem Mass Spectrometry in Diagnosis and Management of Inborn Errors of Metabolism
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Kannan Vaidyanathan, Sandhya Gopalakrishnan
Leigh syndrome is caused due to mutations in the protein coding gene, NDUFS4; (NADH dehydrogenase ubiquinone Fe-S protein 4). This protein is part of the mitochondrial Complex I, comprising 45 sub-units encoded by mitochondrial and nuclear genes. A recessive mouse phenotype was developed by inclusion of a transposable element into Ndufs4, and the resultant metabolite analysis of the model revealed increased hydroxyacylcarnitine species leading to imbalanced NADH/NAD(+) ratio which inhibited mitochondrial beta oxidation [53]. Proteomic analysis showed that the genes encoding acetyl-coA carboxylase beta, M-cadherin, calpain III, creatine kinase, glycogen synthase (GS), and sarcoplasmic reticulum calcium ATPase 1 (SERCA1) were down-regulated in patients with McArdle disease [54]. Statistically significant decreases were observed for five proteins following enzyme replacement therapy in patients with Fabry disease, namely, alpha(2)-HS glycoprotein, vitamin D-binding protein, transferrin, Ig-alpha-2 C chain, and alpha-2-antiplasmin [55].
Clinical Manifestation of Mitochondrial Disorders in Childhood
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Leigh syndrome (Leigh, 1951) itself has two different meanings. The first represents the radiological or pathological findings of focal bilaterally symmetrical lesions, especially in the thalamus and brainstem regions. The other broadens this meaning to the clinical unit also known as subacute necrotizing encephalomyelopathy. Genetically, LS is very heterogenous and should be defined in by specific mutation or protein deficit where possible, as some particular may specifically differ in their clinical manifestation (e.g., SURF1 or pyruvate-dehydrogenase complex deficiency). In general, LS may be caused by deficits of respiratory chain complex subunits (complex I, II, IV, and V) and their cofactors (e.g., co-enzyme Q10), mutations in nDNA (e.g., SCO2, SURF1), mtDNA encoded tRNA, or the pyruvate dehydrogenase complex (Loeffen et al., 2000; Finsterer, 2008). Mitochondrial respiratory chain complex I (nicotinamide adenine dinucleotide-ubiquinone oxidoreductase) is the largest enzymatic complex of the mitochondrial respiratory chain. Defects in complex I due to nuclear DNA mutations are one of the most frequent casuses of LS. Various mutations in subunits of complex I encoded by nDNA (NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, and NDUFS8 were reported (Marin et al., 2013).
Genome-wide association studies of stress score in a Korean Cohort
Published in Stress, 2021
In this study, genes that increase susceptibility to stress were identified using results from a stress survey. In terms of the risk of stress, a score was calculated from the sum of all survey results. Following this, the group of subjects who scored within a range in which a higher proportion of insomnia was present were defined as High Stress and analyzed. Although no significant genetic indicator at the genome-wide significant level was found in this study, indicators at the genome-wide suggestive level were identified, reflecting high potential. The most significant SNP of GenST (rs9353437) was found in an epidermal growth factor gene (eyes shut homolog, EYS) and expressed in the photoreceptor layer of the retina. The GWAS results of PhyST showed a significant SNP (rs4924370) in a spliceosomal factor (Aquarius intron-binding spliceosomal factor, AQR). Notably, the second most significant SNP (rs1991002) was found in an oxidoreductase gene (NADH:Ubiquinone Oxidoreductase Subunit S4, NDUFS4) and was marginally associated (p-value < 0.05) with GenST, MenST, and ActST.
Gene expression study of mitochondrial complex I in schizophrenia and paranoid personality disorder
Published in The World Journal of Biological Psychiatry, 2018
Arvin Haghighatfard, Sarah Andalib, Mozhdeh Amini Faskhodi, Soha Sadeghi, Amir Hossein Ghaderi, Shadi Moradkhani, Jalal Rostampour, Zeinab Tabrizi, Ali Mahmoodi, Talie Karimi, Zakieh Ghadimi
In present study, expression changes of 18 genes in SCZ patients and 11 genes in PPD patients were detected in mitochondrial complex I. Expression levels of NDUFS1, NDUFS4, NDUFV1, NDUFV2, NDUFB2, NDUFB5, NDUFB9, NDUFA5, NDUFA8, NDUFA13 and NDUFC1 were up-regulated and expression levels of NDUFAB1, NDUFB10, NDUFB11, NDUFA1, NDUFA2, NDUFS7 and NDUFS8 were down-regulated in chronic schizophrenic patients in comparison with non-psychiatric individuals. Also, expression levels of NDUFS1, NDUFV1, NDUFV2, NDUFB5, NDUFB9, NDUFA13, NDUFA8 and NDUFA5 were up-regulated and NDUFB11, NDUFS7 and NDUFS8 were down-regulated in the PPD group in comparison with the non-psychiatric group. Significant over-expression of NDUFS1 was found in paranoid schizophrenic (n = 297) and PPD patients (n = 340) in comparison with other subtypes of SCZ (total n = 337). Gene expression results are presented in Table 2 and Figures 2 and 3, which show a heat map of gene expression levels in group comparisons.
The preclinical discovery and development of paliperidone for the treatment of schizophrenia
Published in Expert Opinion on Drug Discovery, 2020
Anna Wesołowska, Magdalena Jastrzębska-Więsek, Agnieszka Cios, Anna Partyka
Intracellular calcium signaling, energy metabolism, and neuronal plasticity can be influenced by inducing axonal remodeling and by increasing the levels of certain synaptic proteins. Synaptoneurosomal-enriched preparations were obtained from rat prefrontal cortex (PFC) after chronic treatment (28 days) with paliperidone (1 mg/kg) and lithium by Corena-McLeod et al. [41]. Similar protein expression profiles, observed for paliperidone and lithium at the synaptoneurosomal level, may suggest the same mode of action for both medicines. The common pathways affected by these two drugs included oxidative phosphorylation, electron transport, carbohydrate metabolism, and postsynaptic cytokinesis, implicating the effects of both drugs in signaling pathways, energy metabolism, and synaptic plasticity. Hence, authors proposed the mood-stabilizing activity for paliperidone [41]. However, after 28 days of administration with paliperidone or risperidone to rats, opposite changes in the expression of selected subunits of complexes from the electron transport chain were observed in PFC synaptoneurosomal preparations. Some proteins remained unchanged, while some others were upregulated by paliperidone unlike risperidone. Among them, mitochondrial proteins NDUFS4 (complex I) and ATP5A1 (complex V), whose expressions are altered in postmortem brain of schizophrenic and bipolar subjects [42], were differently regulated by paliperidone and risperidone [43]. Moreover, paliperidone, similarly to lithium, exhibited a substantial and common effect on the phosphorylation state of specific actin, tubulin, and myosin isoforms as well as on the other proteins associated with neurofilaments. Furthermore, different subunits from complex III and V of the electron transfer chain were heavily phosphorylated following treatment with these drugs, indicating selective phosphorylation and confirming such mode of action for mood stabilizers [44]. Phosphorylation of actin and tubulin, related to mitochondrial migration, was oppositely regulated by paliperidone and risperidone in PFC synaptoneurosomal preparations [6], which translates into various intracellular consequences in calcium homeostasis and neuronal firing and is finally reflected in clinical implications.