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Redox Regulation of Cobalamin Status...

Zhang, Yiting.

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Redox Regulation of Cobalamin Status in Human Neuronal Cells and Cerebral Cortex: Implications for Aging, Autism and Schizophrenia.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Redox Regulation of Cobalamin Status in Human Neuronal Cells and Cerebral Cortex: Implications for Aging, Autism and Schizophrenia./
Author:	Zhang, Yiting.
Description:	153 p.
Notes:	Source: Dissertation Abstracts International, Volume: 77-11(E), Section: B.
Contained By:	Dissertation Abstracts International77-11B(E).
Subject:	Pharmaceutical sciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10133328
ISBN:	9781339919089

Redox Regulation of Cobalamin Status in Human Neuronal Cells and Cerebral Cortex: Implications for Aging, Autism and Schizophrenia.
Zhang, Yiting.

Redox Regulation of Cobalamin Status in Human Neuronal Cells and Cerebral Cortex: Implications for Aging, Autism and Schizophrenia. - 153 p.

Source: Dissertation Abstracts International, Volume: 77-11(E), Section: B.

Thesis (Ph.D.)--Northeastern University, 2016.

Cobalamin (Cbl), also known as vitamin B12, is an essential micronutrient which mammals must acquire through diet. It is a critical cofactor for two metabolic reactions in its active forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). MeCbl is the cofactor for folate-dependent methylation of homocysteine (HCY) to methionine by methionine synthase (MS) in the cytoplasm, and AdoCbl is the cofactor for conversion of methylmalonylCoA to succinylCoA by methylmalonyl CoA mutase (MCM) in mitochondria. Since MS activity determines the ratio of the methyl donor S-adenosylmethionine (SAM) to the endogenous methylation inhibitor S-adenosylhomocysteine (SAH), MeCbl is poised to influence hundreds of SAM-dependent methylation reactions, affecting nearly every aspect of metabolism. Important among these reactions is methylation of DNA and histones, which combine to exert dynamic epigenetic control over gene expression and plays a crucial role in brain development.

ISBN: 9781339919089Subjects--Topical Terms:

3173021
Pharmaceutical sciences.

Redox Regulation of Cobalamin Status in Human Neuronal Cells and Cerebral Cortex: Implications for Aging, Autism and Schizophrenia.
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020 $a 9781339919089
035 $a (MiAaPQ)AAI10133328
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100 1 $a Zhang, Yiting. $3 3189665
245 1 0 $a Redox Regulation of Cobalamin Status in Human Neuronal Cells and Cerebral Cortex: Implications for Aging, Autism and Schizophrenia.
300 $a 153 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-11(E), Section: B.
500 $a Adviser: Richard Carlton Deth.
502 $a Thesis (Ph.D.)--Northeastern University, 2016.
520 $a Cobalamin (Cbl), also known as vitamin B12, is an essential micronutrient which mammals must acquire through diet. It is a critical cofactor for two metabolic reactions in its active forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). MeCbl is the cofactor for folate-dependent methylation of homocysteine (HCY) to methionine by methionine synthase (MS) in the cytoplasm, and AdoCbl is the cofactor for conversion of methylmalonylCoA to succinylCoA by methylmalonyl CoA mutase (MCM) in mitochondria. Since MS activity determines the ratio of the methyl donor S-adenosylmethionine (SAM) to the endogenous methylation inhibitor S-adenosylhomocysteine (SAH), MeCbl is poised to influence hundreds of SAM-dependent methylation reactions, affecting nearly every aspect of metabolism. Important among these reactions is methylation of DNA and histones, which combine to exert dynamic epigenetic control over gene expression and plays a crucial role in brain development.
520 $a Neurologic dysfunction is a primary clinical manifestation of Cbl deficiency and cerebral sequelae of Cbl deficiency include impaired cognition and memory, as well as mood disorders. The structure of Cbl contains a corrin ring and at the center of the ring is a cobalt atom which can be linked to different ligands in the upper beta-axial position, giving rise to different Cbl species. By developing a novel HPLC/electrochemical detection-based assay, I measured the levels of six different naturally occurring Cbl species including AdoCbl and MeCbl, in postmortem human frontal cortex of control subjects, from 19 weeks of fetal development through 80 years of age, and subjects with autism or schizophrenia. Results showed that levels of total Cbl and active Cbl species were significantly decreased in older control subjects (>60 yrs of age) as well as in autistic and schizophrenic subjects.
520 $a Oxidative stress as indicated by low level of primary cellular antioxidant glutathione (GSH) has been highlighted in aging and neurological disorders including autism and schizophrenia. Cbl deficiency can be caused by dietary insufficiency, malabsorption or defective intracellular Cbl processing, all of which eventually lead to inadequate of synthesis of metabolically active Cbl species. Using both the SH-SY5Y human neuroblastoma cell line as a neuronal cell model and a knock-out mouse model with low GSH level, my results revealed that neuronal Cbl metabolism was redox-dependent and oxidative stress impaired the cellular Cbl uptake and the formation of active Cbl species from inactive species, suggesting that oxidative stress may lead to the dramatic reduction of Cbl previously identified in aging, autism and schizophrenia.
520 $a Neuregulin-1 (NRG-1) is an epidermal growth factor (EGF)-like growth factor that plays critical roles in development of the central nervous system, as well as maintaining its normal function. Decreased levels of NRG-1 and its receptor ErbB4 are observed in prefrontal cortex of patients with schizophrenia and the NRG-1 gene has been identified as a leading susceptibility locus for schizophrenia. NRG-1 treatment of SH-SY5Y cells in my studies showed that NRG-1 stimulated neuronal synthesis of AdoCbl and MeCbl by both promoting conversion of inactive to active Cbl species and increasing neuronal Cbl uptake. Further studies revealed that NRG-1 achieved these effects by stimulating excitatory amino acid transporter-3 (EAAT3)-mediated cysteine uptake and cysteine-dependent GSH synthesis.
520 $a Since the brain is present in a unique redox environment and both selenium-containing selenoproteins and GSH play important roles in the brain redox system, the effects of GSH-biased and selenium-biased redox conditions on neuronal cobalamin metabolism have also been investigated. Results showed that cellular Cbl uptake was impaired under oxidative stress conditions and synthesis of active Cbl species was impaired when extracellular cysteine and selenium were scarce.
520 $a These findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect adaptation to increasing antioxidant demand, while accelerated deficits may contribute to neurodevelopmental and neuropsychiatric disorders. In vitro and in vivo studies not only identify novel neuroprotective roles for NRG-1 in terms of stimulating antioxidant and Cbl synthesis, but also reveal the role of cellular redox status in regulating Cbl metabolism and its related pathways. Overall, this thesis addresses the role of Cbl in brain function and neurological disorders, identifies the underlying regulatory mechanism of brain Cbl metabolism and provides a potential mechanistic link between Cbl deficiency and neurological disorders. Together these results may aid in the improvement of our understanding about the neurological role of Cbl.
590 $a School code: 0160.
650 4 $a Pharmaceutical sciences. $3 3173021
650 4 $a Pharmacology. $3 634543
650 4 $a Aging. $3 543123
650 4 $a Psychobiology. $3 555678
690 $a 0572
690 $a 0419
690 $a 0493
690 $a 0349
710 2 $a Northeastern University. $b Pharmaceutical Sciences. $3 1674814
773 0 $t Dissertation Abstracts International $g 77-11B(E).
790 $a 0160
791 $a Ph.D.
792 $a 2016
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10133328