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Article ; Online: Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are characterised by differential activation of ER stress pathways: focus on UPR target genes.

Montibeller, L / de Belleroche, J

2018 Volume 23, Issue 5, Page(s) 897–912

Abstract: The endoplasmic reticulum (ER) plays an important role in maintenance of proteostasis through the unfolded protein response (UPR), which is strongly activated in most neurodegenerative disorders. UPR signalling pathways mediated by IRE1α and ATF6 play a ... ...

Abstract	The endoplasmic reticulum (ER) plays an important role in maintenance of proteostasis through the unfolded protein response (UPR), which is strongly activated in most neurodegenerative disorders. UPR signalling pathways mediated by IRE1α and ATF6 play a crucial role in the maintenance of ER homeostasis through the transactivation of an array of transcription factors. When activated, these transcription factors induce the expression of genes involved in protein folding and degradation with pro-survival effects. However, the specific contribution of these transcription factors to different neurodegenerative diseases remains poorly defined. Here, we characterised 44 target genes strongly influenced by XBP1 and ATF6 and quantified the expression of a subset of genes in the human post-mortem spinal cord from amyotrophic lateral sclerosis (ALS) cases and in the frontal and temporal cortex from frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) cases and controls. We found that IRE1α-XBP1 and ATF6 pathways were strongly activated both in ALS and AD. In ALS, XBP1 and ATF6 activation was confirmed by a substantial increase in the expression of both known and novel target genes involved particularly in co-chaperone activity and ER-associated degradation (ERAD) such as DNAJB9, SEL1L and OS9. In AD cases, a distinct pattern emerged, where targets involved in protein folding were more prominent, such as CANX, PDIA3 and PDIA6. These results reveal that both overlapping and disease-specific patterns of IRE1α-XBP1 and ATF6 target genes are activated in AD and ALS, which may be relevant to the development of new therapeutic strategies. Graphical abstract The endoplasmic reticulum (ER) plays an important role in maintenance of proteostasis through the unfolded protein response (UPR). Two major UPR signalling pathways are mediated by IRE1α and ATF6. Here, we demonstrate that these pathways activate differential gene sets in human post-mortem tissues derived from amyotrophic lateral sclerosis (ALS) compared to Alzheimer's disease (AD) cases. Our results identify IRE1α and ATF6 specific targets that can have major implications in the development of new therapeutic strategies and potential biomarkers.
MeSH term(s)	Activating Transcription Factor 6/metabolism ; Adult ; Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Endoplasmic Reticulum Stress/genetics ; Endoribonucleases/metabolism ; Frontal Lobe/metabolism ; Frontotemporal Lobar Degeneration/genetics ; Frontotemporal Lobar Degeneration/metabolism ; Humans ; Middle Aged ; Protein Serine-Threonine Kinases/metabolism ; Response Elements ; Spinal Cord/metabolism ; Temporal Lobe/metabolism ; Transcriptional Activation ; Unfolded Protein Response/genetics ; X-Box Binding Protein 1/metabolism ; Young Adult
Chemical Substances	ATF6 protein, human ; Activating Transcription Factor 6 ; X-Box Binding Protein 1 ; XBP1 protein, human ; ERN1 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-)
Language	English
Publishing date	2018-05-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1362749-1
ISSN	1466-1268 ; 1355-8145
ISSN (online)	1466-1268
ISSN	1355-8145
DOI	10.1007/s12192-018-0897-y
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Zs.A 4797: Show issues

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Article: Variants in the zinc transporter-3 encoding gene (SLC30A3) in schizophrenia and bipolar disorder: Effects on brain glutamate-A pilot study.

Jelen, Luke A / Green, Mark S / King, Sinead / Morris, Alex G / Zhang, Xinyuan / Lythgoe, David J / Young, Allan H / De Belleroche, Jacqueline / Stone, James M

Frontiers in psychiatry

2022 Volume 13, Page(s) 929306

Abstract: Zinc transporter 3 (ZnT3) has been implicated in the aetiopathology of schizophrenia. In this pilot study, we tested the hypothesis that the presence of a minor allele of two variants in the gene encoding ZnT3 (SLC30A3) affects brain glutamate and ... ...

Abstract	Zinc transporter 3 (ZnT3) has been implicated in the aetiopathology of schizophrenia. In this pilot study, we tested the hypothesis that the presence of a minor allele of two variants in the gene encoding ZnT3 (SLC30A3) affects brain glutamate and cognitive activity in patients with schizophrenia and bipolar affective disorder. Fifteen patients with schizophrenia (SCZ), 15 with bipolar affective disorder type 2 (BD), and 14 healthy volunteers (HV) were genotyped for two SLC30A3 single nucleotide polymorphisms (rs11126936 and rs11126929). They also underwent structural and functional MRI (n-back) imaging as well as static (PRESS) and functional magnetic resonance spectroscopy (n-back) on a 3 Tesla MRI system. SCZ with at least one copy of the minor allele showed reductions in dorsal anterior cingulate cortex glutamate during the n-back task, whereas SCZ without the minor allele showed an increase in glutamate. BD with the minor allele had reduced glutamate in the anterior cingulate cortex (
Language	English
Publishing date	2022-09-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564218-2
ISSN	1664-0640
ISSN	1664-0640
DOI	10.3389/fpsyt.2022.929306
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Article: Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS).

Kondori, Nazanin R / Paul, Praveen / Robbins, Jacqueline P / Liu, Ke / Hildyard, John C W / Wells, Dominic J / de Belleroche, Jacqueline S

Frontiers in molecular biosciences

2018 Volume 5, Page(s) 8

Abstract: We have investigated a pathogenic mutation in D-amino acid oxidase (DAO), ... ...

Abstract	We have investigated a pathogenic mutation in D-amino acid oxidase (DAO), DAO
Language	English
Publishing date	2018-02-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2018.00008
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Article ; Online: Common variants in the chromosome 2p23 region containing the SLC30A3 (ZnT3) gene are associated with schizophrenia in female but not male individuals in a large collection of European samples.

Perez-Becerril, C / Morris, A G / Mortimer, A / McKenna, P J / de Belleroche, J

Psychiatry research

2016 Volume 246, Page(s) 335–340

Abstract: Previously, we found a significant gender-specific association of schizophrenia, in a UK case/control study, with SLC30A3, a candidate that is consistently down-regulated in schizophrenia in two independent cohorts. In view of the potential significance ... ...

Abstract	Previously, we found a significant gender-specific association of schizophrenia, in a UK case/control study, with SLC30A3, a candidate that is consistently down-regulated in schizophrenia in two independent cohorts. In view of the potential significance of this finding, we extended this study to a larger cohort using GWAS data from the Psychiatric Genetic Consortium (PGC). Meta-analysis was performed for the only two SLC30A3 SNP variants (rs11126936 and rs11126929) available in most PGC cohorts. A significant association with schizophrenia was found for both variants. When meta-analysis was performed in male and female case-control subsets, an increased and gender-specific effect of allele on risk of disease was found in females for both SNPs with no significant effect in males, which was further associated with a gender-specific effect on gene expression. In conclusion, using a large European-wide sample we were able to replicate the gender-specific association previously found in a UK cohort.
MeSH term(s)	Case-Control Studies ; Cation Transport Proteins/genetics ; Europe ; Female ; Genome-Wide Association Study ; Humans ; Male ; Schizophrenia/genetics ; Sex Factors
Chemical Substances	Cation Transport Proteins ; SLC30A3 protein, human
Language	English
Publishing date	2016-09-28
Publishing country	Ireland
Document type	Journal Article ; Meta-Analysis
ZDB-ID	445361-x
ISSN	1872-7123 ; 1872-7506 ; 0925-4927 ; 0165-1781
ISSN (online)	1872-7123 ; 1872-7506
ISSN	0925-4927 ; 0165-1781
DOI	10.1016/j.psychres.2016.09.052
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Zs.A 1541: Show issues

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Article ; Online: d-Amino acids: new clinical pathways for brain diseases.

Souza, Isis Nem de Oliveira / Roychaudhuri, Robin / de Belleroche, Jacqueline / Mothet, Jean-Pierre

Trends in molecular medicine

2023 Volume 29, Issue 12, Page(s) 1014–1028

Abstract: Free d-amino acids (d-AAs) are emerging as a novel and important class of signaling molecules in many organs, including the brain and endocrine systems. There has been considerable progress in our understanding of the fundamental roles of these atypical ... ...

Abstract	Free d-amino acids (d-AAs) are emerging as a novel and important class of signaling molecules in many organs, including the brain and endocrine systems. There has been considerable progress in our understanding of the fundamental roles of these atypical messengers, with increasingly recognized implications in a wide range of neuropathologies, including schizophrenia (SCZ), epilepsy, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), substance abuse, and chronic pain, among others. Research has enabled the discovery that d-serine, d-aspartate and more recently d-cysteine are essential for the healthy development and function of the central nervous system (CNS). We discuss recent progress that has profoundly transformed our vision of numerous physiological processes but has also shown how d-AAs are now offering therapeutic promise in clinical settings for several human diseases.
MeSH term(s)	Humans ; Amino Acids/metabolism ; Critical Pathways ; Central Nervous System/metabolism ; Brain/metabolism ; Alzheimer Disease/metabolism
Chemical Substances	Amino Acids
Language	English
Publishing date	2023-09-26
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2023.09.001
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Zs.A 4345: Show issues

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Article ; Online: Characterisation of the pathogenic effects of the in vivo expression of an ALS-linked mutation in D-amino acid oxidase: Phenotype and loss of spinal cord motor neurons.

Kondori, Nazanin Rahmani / Paul, Praveen / Robbins, Jacqueline P / Liu, Ke / Hildyard, John C W / Wells, Dominic J / de Belleroche, Jacqueline S

PloS one

2017 Volume 12, Issue 12, Page(s) e0188912

Abstract: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disorder characterised by selective loss of motor neurons leading to fatal paralysis. Current therapeutic approaches are limited in their effectiveness. Substantial advances ...

Abstract	Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disorder characterised by selective loss of motor neurons leading to fatal paralysis. Current therapeutic approaches are limited in their effectiveness. Substantial advances in understanding ALS disease mechanisms has come from the identification of pathogenic mutations in dominantly inherited familial ALS (FALS). We previously reported a coding mutation in D-amino acid oxidase (DAOR199W) associated with FALS. DAO metabolises D-serine, an essential co-agonist at the N-Methyl-D-aspartic acid glutamate receptor subtype (NMDAR). Using primary motor neuron cultures or motor neuron cell lines we demonstrated that expression of DAOR199W, promoted the formation of ubiquitinated protein aggregates, activated autophagy and increased apoptosis. The aim of this study was to characterise the effects of DAOR199W in vivo, using transgenic mice overexpressing DAOR199W. Marked abnormal motor features, e.g. kyphosis, were evident in mice expressing DAOR199W, which were associated with a significant loss (19%) of lumbar spinal cord motor neurons, analysed at 14 months. When separated by gender, this effect was greater in females (26%; p< 0.0132). In addition, we crossed the DAOR199W transgenic mouse line with the SOD1G93A mouse model of ALS to determine whether the effects of SOD1G93A were potentiated in the double transgenic line (DAOR199W/SOD1G93A). Although overall survival was not affected, onset of neurological signs was significantly earlier in female double transgenic animals than their female SOD1G93A littermates (125 days vs 131 days, P = 0.0239). In summary, some significant in vivo effects of DAOR199W on motor neuron function (i.e. kyphosis and loss of motor neurons) were detected which were most marked in females and could contribute to the earlier onset of neurological signs in double transgenic females compared to SOD1G93A littermates, highlighting the importance of recognizing gender effects present in animal models of ALS.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Body Weight ; D-Amino-Acid Oxidase/genetics ; Mice ; Mice, Transgenic ; Motor Neurons/pathology ; Mutation ; Phenotype ; Spinal Cord/pathology
Chemical Substances	Dao1 protein, mouse (EC 1.4.3.-) ; D-Amino-Acid Oxidase (EC 1.4.3.3)
Language	English
Publishing date	2017-12-01
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0188912
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Article ; Online: Allelic variants in the zinc transporter-3 gene, SLC30A3, a candidate gene identified from gene expression studies, show gender-specific association with schizophrenia.

Perez-Becerril, C / Morris, A G / Mortimer, A / McKenna, P J / de Belleroche, J

European psychiatry : the journal of the Association of European Psychiatrists

2013 Volume 29, Issue 3, Page(s) 172–178

Abstract: Previous microarray analysis of gene expression in frontal cortex showed differential expression of genes associated with synaptic function in schizophrenia compared to matched-controls in two independent cohorts. One of these genes validated in both ... ...

Abstract	Previous microarray analysis of gene expression in frontal cortex showed differential expression of genes associated with synaptic function in schizophrenia compared to matched-controls in two independent cohorts. One of these genes validated in both cohorts, SLC30A3, which encodes the Zinc Transporter 3 (ZNT3), is localised to synaptic vesicles in glutamate synapses and known to be involved in cognitive function. In view of the robust depletion of SLC30A3 mRNA in two independent studies and the importance of this gene in cognitive function, we investigated whether single nucleotide polymorphism (SNP) associations with schizophrenia could be detected in a UK case controlled schizophrenia cohort. Four SNPs were selected across this gene and genotyped in a cohort of cases and controls from East UK. We found significant associations with schizophrenia at the allelic (ORs: 1.51 to 1.57), genotype (ORs: 1.46 to 1.53) and haplotype level (P=2.15×10(-4)). These associations proved to be gender-specific with significant effects of allele (ORs: 1.74 to 2.11), genotype (ORs: 1.78 to 2.14) and haplotype (P=3.51×10(-5)) observed in female schizophrenia cases but not males, when split by gender. In conclusion, SNPs in SLC30A3 showed a gender-specific association with schizophrenia in this East UK cohort, which merits further investigation in other population samples.
MeSH term(s)	Alleles ; Case-Control Studies ; Cation Transport Proteins/genetics ; Cohort Studies ; England/epidemiology ; Female ; Genome-Wide Association Study ; Genotype ; Haplotypes/genetics ; Humans ; Male ; Polymorphism, Single Nucleotide/genetics ; Schizophrenia/epidemiology ; Schizophrenia/genetics ; Sex Factors
Chemical Substances	Cation Transport Proteins ; SLC30A3 protein, human
Language	English
Publishing date	2013-07-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1074337-6
ISSN	1778-3585 ; 0767-399X ; 0924-9338
ISSN (online)	1778-3585
ISSN	0767-399X ; 0924-9338
DOI	10.1016/j.eurpsy.2013.05.007
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Zs.A 2369: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 558: Show issues

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Article: Platelet serotonin pathway in menstrual migraine.

de Belleroche, J

Cephalalgia : an international journal of headache

1996 Volume 16, Issue 6, Page(s) 406

MeSH term(s)	Blood Platelets/physiology ; Female ; Humans ; Menstrual Cycle/physiology ; Menstruation Disturbances/physiopathology ; Migraine Disorders/physiopathology ; Monoamine Oxidase/blood ; Serotonin/physiology
Chemical Substances	Serotonin (333DO1RDJY) ; Monoamine Oxidase (EC 1.4.3.4)
Language	English
Publishing date	1996-10
Publishing country	England
Document type	Comment ; Editorial
ZDB-ID	604567-4
ISSN	0333-1024
ISSN	0333-1024
DOI	10.1046/j.1468-2982.1996.1606405-3.x
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Zs.A 1645: Show issues

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Article: Cholecystokinin release in the central nervous system.

de Belleroche, J

Neurochemistry international

1993 Volume 22, Issue 6, Page(s) 529

MeSH term(s)	Animals ; Anxiety/physiopathology ; Brain/metabolism ; Cholecystokinin/metabolism ; Dopamine/physiology ; Serotonin/physiology
Chemical Substances	Serotonin (333DO1RDJY) ; Cholecystokinin (9011-97-6) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	1993-06
Publishing country	England
Document type	Comment ; Journal Article
ZDB-ID	283190-9
ISSN	1872-9754 ; 0197-0186
ISSN (online)	1872-9754
ISSN	0197-0186
DOI	10.1016/0197-0186(93)90026-2
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Zs.A 1610: Show issues

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Article ; Online: Experimental approaches for elucidating co-agonist regulation of NMDA receptor in motor neurons: Therapeutic implications for amyotrophic lateral sclerosis (ALS).

Paul, Praveen / de Belleroche, Jackie

Journal of pharmaceutical and biomedical analysis

2015 Volume 116, Page(s) 2–6

Abstract: Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterised by selective loss of motor neurons leading to fatal paralysis. Although most cases are sporadic, approximately 10% of cases are familial and the identification of mutations in ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterised by selective loss of motor neurons leading to fatal paralysis. Although most cases are sporadic, approximately 10% of cases are familial and the identification of mutations in these kindred has greatly accelerated our understanding of disease mechanisms. To date, the causal genes in over 70% of these families have been identified. Recently, we reported a mutation (R199W) in the enzyme that degrades d-serine, D-amino acid oxidase (DAO) and co-segregates with disease in familial ALS. Moreover, D-serine and DAO are abundant in human spinal cord and severely depleted in ALS. Using cell culture models, we have defined the effects of R199W-DAO, and shown that it activates autophagy, leads to the formation of ubiquitinated protein aggregates and promotes apoptosis, all of which processes are attenuated by a D-serine/glycine site antagonist of the N-methyl D-aspartate receptor (NMDAR). These findings suggest that the toxic effects of R199W-DAO are at least in part mediated via the NMDAR involving the D-serine/glycine site and that an excitotoxic mechanism may contribute to disease pathogenesis.
MeSH term(s)	Amyotrophic Lateral Sclerosis/drug therapy ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; D-Amino-Acid Oxidase/genetics ; D-Amino-Acid Oxidase/metabolism ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Amino Acid Agonists/therapeutic use ; Humans ; Motor Neurons/drug effects ; Motor Neurons/physiology ; Receptors, N-Methyl-D-Aspartate/agonists ; Receptors, N-Methyl-D-Aspartate/physiology ; Serine/genetics ; Serine/metabolism
Chemical Substances	Excitatory Amino Acid Agonists ; Receptors, N-Methyl-D-Aspartate ; Serine (452VLY9402) ; D-Amino-Acid Oxidase (EC 1.4.3.3)
Language	English
Publishing date	2015-01-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	604917-5
ISSN	1873-264X ; 0731-7085
ISSN (online)	1873-264X
ISSN	0731-7085
DOI	10.1016/j.jpba.2014.12.040
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Zs.A 1850: Show issues

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