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Aggregation and catabolism of disease-associated intra-Abeta mutations: reduced proteolysis of AbetaA21G by neprilysin.

https://arctichealth.org/en/permalink/ahliterature156321
Source
Neurobiol Dis. 2008 Sep;31(3):442-50
Publication Type
Article
Date
Sep-2008
Author
Vicki Betts
Malcolm A Leissring
Georgia Dolios
Rong Wang
Dennis J Selkoe
Dominic M Walsh
Author Affiliation
Laboratory for Neurodegenerative Research, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Republic of Ireland.
Source
Neurobiol Dis. 2008 Sep;31(3):442-50
Date
Sep-2008
Language
English
Publication Type
Article
Keywords
Alzheimer Disease - genetics - metabolism - physiopathology
Amino Acid Sequence - genetics
Amino Acid Substitution - genetics
Amyloid beta-Peptides - chemistry - genetics - metabolism
Amyloid beta-Protein Precursor - chemistry - genetics - metabolism
Brain Chemistry - genetics
Fibrinolysin - chemistry - metabolism
Humans
Insulysin - chemistry - metabolism
Mass Spectrometry
Mutation - genetics
Neprilysin - chemistry - metabolism
Peptide Fragments - chemistry - genetics - metabolism
Peptide Hydrolases - metabolism
Plaque, Amyloid - chemistry - metabolism
Protein Structure, Tertiary - genetics
Abstract
Five point mutations within the amyloid beta-protein (Abeta) sequence of the APP gene are associated with hereditary diseases which are similar or identical to Alzheimer's disease and encode: the A21G (Flemish), E22G (Arctic), E22K (Italian), E22Q (Dutch) and the D23N (Iowa) amino acid substitutions. Although a substantial body of data exists on the effects of these mutations on Abeta production, whether or not intra-Abeta mutations alter degradation and how this relates to their aggregation state remain unclear. Here we report that the E22G, E22Q and the D23N substitutions significantly increase fibril nucleation and extension, whereas the E22K substitution exhibits only an increased rate of extension and the A21G substitution actually causes a decrease in the extension rate. These substantial differences in aggregation together with our observation that aggregated wild type Abeta(1-40) was much less well degraded than monomeric wild type Abeta(1-40), prompted us to assess whether or not disease-associated intra-Abeta mutations alter proteolysis independent of their effects on aggregation. Neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin play a major role in Abeta catabolism, therefore we compared the ability of these enzymes to degrade wild type and mutant monomeric Abeta peptides. Experiments investigating proteolysis revealed that all monomeric peptides are degraded similarly by IDE and plasmin, but that the Flemish peptide was degraded significantly more slowly by NEP than wild type Abeta or any of the other mutant peptides. This finding suggests that resistance to NEP-mediated proteolysis may underlie the pathogenicity associated with the A21G mutation.
Notes
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PubMed ID
18602473 View in PubMed
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BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse ethnic groups.

https://arctichealth.org/en/permalink/ahliterature165588
Source
Neurosci Lett. 2007 Mar 19;415(1):59-63
Publication Type
Article
Date
Mar-19-2007
Author
G. Xiromerisiou
G M Hadjigeorgiou
J. Eerola
H H Fernandez
V. Tsimourtou
R. Mandel
O. Hellström
K. Gwinn-Hardy
M S Okun
P J Tienari
A B Singleton
Author Affiliation
Neurogenetics Unit, Department of Neurology, University of Thessaly, Medical School, Papakyriazi 22 Street, Larissa 41222, Greece, and Helsinki University Centeral Hospital, Finland.
Source
Neurosci Lett. 2007 Mar 19;415(1):59-63
Date
Mar-19-2007
Language
English
Publication Type
Article
Keywords
Aged
Brain - metabolism - physiopathology
Brain Chemistry - genetics
Brain-Derived Neurotrophic Factor - genetics
Cohort Studies
DNA Mutational Analysis
European Continental Ancestry Group - genetics
Female
Finland - epidemiology
Gene Frequency
Genetic Markers - genetics
Genetic Predisposition to Disease - genetics
Genetic Testing
Genetic Variation - genetics
Genotype
Greece - epidemiology
Haplotypes - genetics
Humans
Male
Middle Aged
North America - epidemiology
Parkinson Disease - ethnology - genetics - metabolism
Polymorphism, Genetic - genetics
Abstract
Experimental and clinical data suggest that genetic variations in brain-derived neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We performed a case-control association analysis of BDNF in three independent Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging SNPs and five constructed haplotypes. No statistically significant differences in genotype and allele frequencies were found between cases and controls in all series. A relatively rare BDNF haplotype showed a trend towards association in the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not detected in the North American series). However, given the large number of comparisons these associations are considered non-significant. In conclusion, our results do not provide statistically significant evidence that common genetic variability in BDNF would associate with the risk for PD in the Caucasian populations studied here.
PubMed ID
17229524 View in PubMed
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Genetic differences in the synthesis and reception of noradrenaline in the mouse brain and behavior in a novel environment.

https://arctichealth.org/en/permalink/ahliterature10390
Source
Neurosci Behav Physiol. 2000 May-Jun;30(3):327-30
Publication Type
Article
Author
N N Dyaglo
G T Shishkina
Author Affiliation
Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, Novosibirsk.
Source
Neurosci Behav Physiol. 2000 May-Jun;30(3):327-30
Language
English
Publication Type
Article
Keywords
Animals
Behavior, Animal - physiology
Brain - anatomy & histology
Brain Chemistry - genetics - physiology
Comparative Study
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred CBA
Norepinephrine - biosynthesis - genetics
Receptors, Adrenergic, alpha-2 - genetics
Species Specificity
Tyrosine 3-Monooxygenase - genetics - metabolism
Abstract
The activity of tyrosine hydroxylase, the key enzyme in catecholamine biosynthesis, was studied along with adrenoceptor density in the brains of male CBA/Lac, BALB/cLac, and C57BL/6J mice, which show different responses to novel environments. C57BL mice showed the highest level of movement activity and the lowest level of emotionality in a novel environment. Mice of this line also showed the highest brainstem tyrosine hydroxylase activity. At the same time, the density of beta-adrenoceptors in the cortex and hypothalamus of C57BL mice was lower than in the other two lines of mice, while the density of alpha2-adrenoceptors in these parts of the brain was lower than in CBA mice. In BALB mice, movement activity was twice as high as in CBA mice, while levels of emotionality were similar in these two lines. Tyrosine hydroxylase activity was higher in the cerebral cortex of BALB mice, while the density of alpha2-adrenoceptors was lower than in CBA mice. These results show that increased investigative activity and decreased emotionality were seen in animals with higher levels of noradrenaline synthesis and decreased density of adrenergic receptors in the brain.
PubMed ID
10970027 View in PubMed
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Human p53 tumor suppressor gene (TP53) and schizophrenia: case-control and family studies.

https://arctichealth.org/en/permalink/ahliterature173686
Source
Neurosci Lett. 2005 Nov 18;388(3):173-8
Publication Type
Article
Date
Nov-18-2005
Author
Xingqun Ni
Joseph Trakalo
Jose Valente
Maria H Azevedo
Michelle T Pato
Carlos N Pato
James L Kennedy
Author Affiliation
Neuroscience Research Department, Neurogenetics Section, Centre for Addiction and Mental Health, 250 College Street, Toronto, Canada M5T 1R8.
Source
Neurosci Lett. 2005 Nov 18;388(3):173-8
Date
Nov-18-2005
Language
English
Publication Type
Article
Keywords
Brain Chemistry - genetics
Case-Control Studies
DNA Mutational Analysis
Female
Gene Frequency - genetics
Genetic Predisposition to Disease - genetics
Genetic Testing
Genotype
Haplotypes
Humans
Linkage Disequilibrium - genetics
Male
Ontario - epidemiology
Polymorphism, Genetic - genetics
Portugal - epidemiology
Schizophrenia - epidemiology - genetics - metabolism
Tumor Suppressor Protein p53 - genetics
Abstract
The human p53 tumor suppressor gene (TP53) is considered as a candidate susceptibility gene for schizophrenia because of its functions in neurodevelopment. To test for an association between TP53 and schizophrenia, both the case-control study and the transmission disequilibrium test (TDT) were performed on genotype data from eight polymorphisms in TP53. Our samples included 286 Toronto schizophrenia cases and 264 controls, and 163 Portuguese nuclear families. In the Toronto case-control study significant differences of allele frequencies of the CAA Ins/Del (p=0.027) and the 16bp Ins/Del (p=0.022) were detected. In TDT analysis we found significant differences for transmission of the CAA Ins/Del (p=0.017) in Portuguese schizophrenia families. Haplotype analysis also showed a significant association between TP53 and schizophrenia. These results provide further evidence that TP53 may play a role in the pathogenesis of schizophrenia.
PubMed ID
16039051 View in PubMed
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Multiple alpha-synuclein gene polymorphisms are associated with Parkinson's disease in a Norwegian population.

https://arctichealth.org/en/permalink/ahliterature157164
Source
Acta Neurol Scand. 2008 Nov;118(5):320-7
Publication Type
Article
Date
Nov-2008
Author
R. Myhre
M. Toft
J. Kachergus
M M Hulihan
J O Aasly
H. Klungland
M J Farrer
Author Affiliation
Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway. ronny.myhre@ntnu.no
Source
Acta Neurol Scand. 2008 Nov;118(5):320-7
Date
Nov-2008
Language
English
Publication Type
Article
Keywords
3' Untranslated Regions - genetics
Aged
Aged, 80 and over
Brain - metabolism - physiopathology
Brain Chemistry - genetics
Case-Control Studies
DNA Mutational Analysis
Female
Gene Frequency - genetics
Genetic Markers - genetics
Genetic Predisposition to Disease - genetics
Genetic Testing
Genotype
Haplotypes - genetics
Humans
Linkage Disequilibrium - genetics
Male
Microsatellite Repeats - genetics
Norway - epidemiology
Parkinson Disease - epidemiology - genetics
Polymorphism, Genetic - genetics
alpha-Synuclein - genetics
Abstract
Previous studies have found associations between Parkinson's disease (PD) and polymorphisms located within both the alpha-synuclein gene (SNCA) promoter and other gene regions. Our aim was to study SNCA gene markers in a closely matched Norwegian PD population to examine the genetic relationship between different polymorphisms associated with the disease.
We genotyped seven single nucleotide polymorphisms (SNPs) located in the SNCA promoter and two SNPs in the 3' gene region and seven microsatellite markers located across the gene in a closely matched series of 236 PD patients and 236 controls. Linkage disequilibrium (LD) structure was examined, and association of single markers and gene haplotypes analyzed.
Several markers located across the SNCA gene were associated with PD, including marker alleles associated with disease in previous studies (Rep1 263-bp allele, rs356165 and rs356219).
LD between associated marker alleles located across the SNCA gene suggests that a single genetic effect might explain the previous reported association in the promoter and 3' regions.
PubMed ID
18485051 View in PubMed
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Seasonal affective disorder and serotonin-related polymorphisms.

https://arctichealth.org/en/permalink/ahliterature46111
Source
Neurobiol Dis. 2001 Apr;8(2):351-7
Publication Type
Article
Date
Apr-2001
Author
C. Johansson
C. Smedh
T. Partonen
P. Pekkarinen
T. Paunio
J. Ekholm
L. Peltonen
D. Lichtermann
J. Palmgren
R. Adolfsson
M. Schalling
Author Affiliation
Neurogenetics Unit, Karolinska Institutet and Karolinska Hospital, Stockholm, S-171 76, Sweden. carolina.johansson@cmm.ki.se
Source
Neurobiol Dis. 2001 Apr;8(2):351-7
Date
Apr-2001
Language
English
Publication Type
Article
Keywords
ATP-Binding Cassette Transporters - genetics - metabolism
Brain - metabolism - physiopathology
Brain Chemistry - genetics
Carrier Proteins - genetics - metabolism
DNA Mutational Analysis
Female
Genetic Predisposition to Disease - genetics
Genetic Screening
Genotype
Humans
Male
Membrane Glycoproteins - genetics - metabolism
Membrane Transport Proteins
Nerve Tissue Proteins
Neurons - metabolism
Polymorphism, Genetic - genetics
Receptor, Serotonin, 5-HT2A
Receptor, Serotonin, 5-HT2C
Receptors, Serotonin - genetics - metabolism
Research Support, Non-U.S. Gov't
Seasonal Affective Disorder - genetics - metabolism - physiopathology
Serotonin - biosynthesis - genetics
Serotonin Plasma Membrane Transport Proteins
Sex Factors
Tyrosine 3-Monooxygenase - genetics - metabolism
Abstract
Disturbances in central serotonergic systems have been hypothesized to be involved in seasonal affective disorder (SAD). Association between SAD and the shorter allele of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR) has been reported in an American sample. We have genotyped 82 SAD patients and 82 healthy controls from Sweden, Finland, and Germany for this and five other polymorphisms in the genes coding for serotonin receptors 5-HT2A and 5-HT2C, tryptophan hydroxylase and white. No associations with SAD or seasonality (seasonal variations in mood and behavior) were detected. Although minor effects cannot be excluded, our results suggest that these polymorphisms do not play a major role in the pathogenesis of SAD in the northern European population.
PubMed ID
11300730 View in PubMed
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Strong genetic evidence for association of TOR1A/TOR1B with idiopathic dystonia.

https://arctichealth.org/en/permalink/ahliterature79642
Source
Neurology. 2006 Nov 28;67(10):1857-9
Publication Type
Article
Date
Nov-28-2006
Author
Kamm C.
Asmus F.
Mueller J.
Mayer P.
Sharma M.
Muller U J
Beckert S.
Ehling R.
Illig T.
Wichmann H E
Poewe W.
Mueller J C
Gasser T.
Author Affiliation
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Hoppe-Seyler-Str. 3, 72086 Tuebingen, Germany.
Source
Neurology. 2006 Nov 28;67(10):1857-9
Date
Nov-28-2006
Language
English
Publication Type
Article
Keywords
Adult
Age Factors
Austria
Brain Chemistry - genetics
DNA Mutational Analysis
Dystonic Disorders - genetics - metabolism - physiopathology
Female
Gene Frequency
Genetic Markers - genetics
Genetic Predisposition to Disease - genetics
Genetic Screening
Genotype
Germany
Haplotypes - genetics
Humans
Male
Molecular Chaperones - genetics
Mutation - genetics
Polymorphism, Single Nucleotide - genetics
Sex Factors
Abstract
Recently, association of a TOR1A(DYT1)/TOR1B risk haplotype with common forms of idiopathic dystonia has been reported in the Icelandic population. Here we report a strong association of two single nucleotide polymorphisms within or in close proximity to the TOR1A 3'UTR, with the lowest p value being 0.000008, in a larger cohort of German and Austrian patients with predominantly focal sporadic dystonia.
PubMed ID
17130424 View in PubMed
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Transmission disequilibrium study of an oligodendrocyte and myelin glycoprotein gene allele in 431 families with an autistic proband.

https://arctichealth.org/en/permalink/ahliterature161094
Source
Neurosci Res. 2007 Dec;59(4):426-30
Publication Type
Article
Date
Dec-2007
Author
Isabelle Martin
Julie Gauthier
Marcello D'Amelio
Sylviane Védrine
Patrick Vourc'h
Guy A Rouleau
Antonio M Persico
Christian R Andres
Author Affiliation
INSERM, U619, Université François-Rabelais de Tours, CHRU de Tours, Faculté de Médecine, 10 Boulevard Tonnellé, BP3223, 37032, Tours Cedex, France.
Source
Neurosci Res. 2007 Dec;59(4):426-30
Date
Dec-2007
Language
English
Publication Type
Article
Keywords
Adolescent
Autistic Disorder - ethnology - genetics - metabolism
Brain Chemistry - genetics
Child
Child, Preschool
Chromosome Mapping
Chromosomes, Human, Pair 17 - genetics
Continental Population Groups
DNA Mutational Analysis
Ethnic Groups
Female
GPI-Linked Proteins
Gene Frequency - genetics
Genetic Markers - genetics
Genetic Predisposition to Disease - genetics
Genetic Testing
Humans
Inheritance Patterns - genetics
Italy
Linkage Disequilibrium - genetics
Male
Myelin Proteins
Myelin-Associated Glycoprotein - genetics
Myelin-Oligodendrocyte Glycoprotein
Quebec
United States
Abstract
Autistic disorder is a neurodevelopmental disorder where genetic factors play an important role. We previously described an association between a subgroup of French autistic patients and an allele of a non-synonymous single nucleotide polymorphism (nsSNP: OMGP62 G>A or rs11080149) in the gene coding for the oligodendrocyte and myelin glycoprotein (OMG), located at 7Mb from the marker D17S250, linked to autism in two independent genome scan studies. We report a study on 431 families with 1 affected child from different origins: French Canada (n=262), Italy (n=123) and United States (n=46). We analyzed the transmission of the rs11080149 alleles from parents to their affected children. There was a preferential transmission of the G allele from parents to affected children (p=0.0017) in the overall sample. Paternal and maternal transmission rates were both skewed. Taking into account our previous results obtained in a French group of patients, where we observed an association with allele A, a direct role of this polymorphism is improbable in autism. The associations observed in Japanese and French patients, the linkage studies and the present work speak in favor of the existence of a susceptibility gene for autism in the NF1 locus.
PubMed ID
17897745 View in PubMed
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9 records – page 1 of 1.