| 1. |
- Landgren, Sara, 1980, et al.
(författare)
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Association of nAChR gene haplotypes with heavy alcohol use and body mass.
- 2009
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Ingår i: Brain research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1305 Suppl
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Tidskriftsartikel (refereegranskat)abstract
- Co-occurring alcohol and nicotine dependence is common, as is alcohol use disorder and overeating. However, major risk genes for these disorders need to be identified. Certain subtypes of the nicotinic acetylcholine receptors in the ventral tegmental area (a reward node) have preclinically been shown to be important for alcohol reward. Therefore the aim was to investigate nicotine receptor subunit genes in a haplotype study of alcohol use. This study includes a Spanish population (n=417) of three groups based on their alcohol consumption; abstainers (n=142), moderate (<280 g/week, n=111) and heavy drinkers (>280 g/week, n=164). 20 tag SNPs in five nicotine receptor subunit genes (CHRNA3, 4, and 6; CHRNB2 and 3) were genotyped and analysed for single marker and haplotype associations. Two haplotypes of the CHRNA6 (CCCC and TCGA) were associated with heavy alcohol consumption (p=0.004 and p=0.035 respectively) and with increased alcohol intake (p=0.004) for the CCCC haplotype compared to non-carriers of these haplotypes. Moreover, one haplotype of the CHRNA4 (GGTG) was associated with increased body weight as compared to non-carriers of this haplotype, especially in the heavy consumers of alcohol (p=0.004).The present findings are the first to disclose a haplotype association between the CHRNA6 gene and heavy alcohol use as well as an association of the CHRNA4 gene with increased body mass in heavy consumers of alcohol. Taken together with previous preclinical data, this targets the nicotinic acetylcholine receptors for development of novel treatment strategies of addictive behaviours, and, more specifically, of a subgroup of individuals with co-morbid alcohol use disorder and overeating.
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| 2. |
- von Otter, Malin, 1978, et al.
(författare)
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Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson's disease.
- 2010
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Ingår i: BMC medical genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oxidative stress is heavily implicated in the pathogenic process of Parkinson's disease. Varying capacity to detoxify radical oxygen species through induction of phase II antioxidant enzymes in substantia nigra may influence disease risk. Here, we hypothesize that variation in NFE2L2 and KEAP1, the genes encoding the two major regulators of the phase II response, may affect the risk of Parkinson's disease. METHODS: The study included a Swedish discovery case-control material (165 cases and 190 controls) and a Polish replication case-control material (192 cases and 192 controls). Eight tag single nucleotide polymorphisms representing the variation in NFE2L2 and three representing the variation in KEAP1 were chosen using HapMap data and were genotyped using TaqMan Allelic Discrimination. RESULTS: We identified a protective NFE2L2 haplotype in both of our European case-control materials. Each haplotype allele was associated with five years later age at onset of the disease (p = 0.001) in the Swedish material, and decreased risk of PD (p = 2 x 10(-6)), with an odds ratio of 0.4 (95% CI 0.3-0.6) for heterozygous and 0.2 (95% CI 0.1-0.4) for homozygous carriers, in the Polish material. The identified haplotype includes a functional promoter haplotype previously associated with high transcriptional activity. Genetic variation in KEAP1 did not show any associations. CONCLUSION: These data suggest that variation in NFE2L2 modifies the Parkinson's disease process and provide another link between oxidative stress and neurodegeneration.
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| 3. |
- von Otter, Malin, 1978, et al.
(författare)
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Kinesin Light Chain 1 Gene Haplotypes in Three Conformational Diseases
- 2010
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Ingår i: NeuroMolecular Medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 12:3, s. 229-236
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Tidskriftsartikel (refereegranskat)abstract
- A functional intracellular transport system is essential to maintain cell shape and function especially in elongated cells, e.g. neurons and lens fibre cells. Impaired intracellular transport has been suggested as a common pathological mechanism for age-related diseases characterised by protein aggregation. Here, we hypothesise that common genetic variation in the transport protein kinesin may influence the risk of Parkinson's disease (PD), Alzheimer's disease (AD) and age-related cataract. This case-control study involves a PD material (165 cases and 190 controls), an AD material (653 cases and 845 controls) and a cataract material (495 cases and 183 controls). Genetic variation in the kinesin light chain 1-encoding gene (KLC1) was tagged by six tag single nucleotide polymorphisms (SNPs). Single SNPs and haplotypes were analysed for associations with disease risk, age parameters, mini-mental state examination scores and cerebrospinal fluid biomarkers for AD using logistic or linear regression. Genetic variation in KLC1 did not influence risk of PD. Weak associations with risk of AD were seen for rs8007903 and rs3212079 (P (c) = 0.04 and P (c) = 0.02, respectively). Two SNPs (rs8007903 and rs8702) influenced risk of cataract (P (c) = 0.0007 and P (c) = 0.04, respectively). However, the allele of rs8007903 that caused increased risk of AD caused reduced risk of cataract, speaking against a common functional effect of this particular SNP in the two diseases. Haplotype analyses did not add significantly to the associations found in the single SNP analyses. Altogether, these results do not convincingly support KLC1 as a major susceptibility gene in any of the studied diseases, although there is a small effect of KLC1 in relation to cataract.
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| 4. |
- Blixt, Åsa, 1960, et al.
(författare)
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Foxe3 is required for morphogenesis and differentiation of the anterior segment of the eye and is sensitive to Pax6 gene dosage.
- 2007
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Ingår i: Developmental biology. - : Elsevier BV. - 0012-1606. ; 302:1, s. 218-29
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Tidskriftsartikel (refereegranskat)abstract
- The dysgenetic lens (dyl) mouse mutant has mutations in Foxe3, which inactivate DNA binding by the encoded forkhead transcription factor. Here we confirm, by targeted inactivation, that Foxe3 mutations are responsible for the dyl phenotype, which include loss of lens epithelium; a small, cataractic lens; and failure of the lens to detach from the surface ectoderm. In contrast to a recent report of targeted Foxe3, we found no phenotypic difference between dyl and Foxe3(-/-) mutants when congenic strains were compared, and thus nothing that argues against Foxe3(dyl) being a null allele. In addition to the lens, most tissues of the anterior segment-iris, cornea, ciliary body and trabecular meshwork-are malformed or show differentiation defects. Many of these abnormalities, such as irido-corneal and irido-lenticular adherences, are present in a less severe form in mice heterozygous for the Foxe3 mutation, in spite of these having an intact lens epithelium. Early Foxe3 expression is highly sensitive to a halved Pax6 gene dosage and there is a striking phenotypic similarity between Pax6 and Foxe3 mutants. We therefore propose that many of the ocular malformations associated with Pax6 haploinsufficiency are consequences of a reduced expression of Foxe3.
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| 5. |
- Landgren, Henrik, 1978
(författare)
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Forkhead Genes in Mammalian Development
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis concerns aspects of Forkhead gene biology and it’s relation to mammalian development. Genes from three subclasses are discussed, Foxj3, Foxf1 and f2, and Foxe3. We have identified and characterized a novel forkhead gene, FoxJ3, that is expressed in neuroectoderm, neural crest and mytome, suggesting possible function in the nervous system and muscle. The myotome, which will develop into muscle, along with the mesenchyme lining the intestinal gut, originates from embryonic mesoderm. Forkhead factors, Foxf1 and Foxf2, are expressed in intestinal mesenchyme derived from splanchnic mesoderm. Foxf function is important for patterning of the gut tube. Removal of Foxf results in a range of intestinal phenotypes, such as agangliosis and megacolon. Both Foxf1 and Foxf2 are regulated by hedgehog signaling, Foxf mutants display mesenchymal increase in Wnt5a expression, and reduction in Bmp4 expression. The extracellular matrix is depleted of collagens, and together with altered paracrine factors, this leads to a phenotype where epithelial cells lose polarization and become resistant to apoptosis. The ocular lens develops from the head ectoderm and a critical factor in its formation is Foxe3. Foxe3 is, after secondary fiber differentiation starts, expressed exclusively in the lens epithelium. These cells provide the precursors for lens fibers. Fiber cells are elongated, terminally differentiated cells that provide the specialized optical properties of the lens. Ectopic expression of Foxe3 in the fiber compartment interferes with several aspects of fiber differentiation. The cytoskeletal remodeling and organelle degradation is blocked in transgenic lenses, whereas fiber cell specific expression of crystallins seems to be undisturbed. Foxe3 is also involved in patterning of the anterior segment of eye. Heterozygous Foxe3 mutants show defects in differentiation of the cornea, iris and filtration angle. The anterior segment similarities in Foxe3 and Pax6 heterozygous mutants provide, along with Foxe3 expression being dependent on Pax6 gene dosage, an indication that Foxe3 is a major contributor to the phenotype of Pax6 mutants.Foxe3 can interact with many signaling pathways active in the eye. Foxe3 expression can be altered by changes in growth factor ligands. Furthermore, components of different growth factor pathways can be controlled by Foxe3. Taken together, Foxe3 biology is regulated on many cellular levels in the ocular lens.
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| 6. |
- Landgren, Henrik, 1978, et al.
(författare)
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FoxJ3, a novel mammalian forkhead gene expressed in neuroectoderm, neural crest, and myotome
- 2004
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Ingår i: Developmental Dynamics. - : Wiley. - 1058-8388 .- 1097-0177. ; 231:2, s. 396-401
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Tidskriftsartikel (refereegranskat)abstract
- Forkhead transcription factors are important regulators of animal development. Here, we describe the embryonic expression pattern for one of the novel forkhead genes that were discovered as a result of the mouse and human genome projects. It is most closely related to FoxJ2 and has been assigned the name FoxJ3. The 100-kb, 13-exon mouse Foxj3 gene on chromosome 4 encodes a 623 amino acid (aa) protein from an mRNA of at least 4.8 kb (Human FOXJ3: Chr 1, 627 aa, 5.3-kb mRNA). During the stages of mouse development investigated (embryonic day [E] 8.5-E12.5) Foxj3 is expressed in neuroectoderm, in neural crest, and in many structures derived from neural crest cells, such as facioacoustic, trigeminal, and dorsal root ganglia. Stripes of expression appear at E10.5 in the location of myotomes and expand ventrally in a pattern similar to the developing body wall musculature. Developing limbs have a complex pattern of Foxj3 expression that at E12.5 colocalizes with the condensed mesenchyme of the skeletal primordia. (C) 2004 Wiley-Liss, Inc.
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| 7. |
- Landgren, Henrik, 1978, et al.
(författare)
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Locating and Labeling Neural Stem Cells in the Brain
- 2011
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Ingår i: JOURNAL OF CELLULAR PHYSIOLOGY. - 0021-9541. ; 226:1, s. 1-7
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Forskningsöversikt (refereegranskat)abstract
- The phenomenon of adult neurogenesis has been demonstrated in most mammals including humans. At least two regions of the adult brain maintain stem cells throughout life; the subgranular zone (SGZ) of the hippocampal dentate gyrus, and the subventricular zone (SVZ) of the lateral ventricle wall. Both regions continuously produce neurons that mature and become integrated into functional networks that are involved in learning and memory and odor discrimination, respectively. Apart from these well-studied regions neurogenesis has been reported in a number of other brain regions, such as amygdala and cortex. However, these studies have been contested and there is currently no well-postulated function for non-SVZ/SGZ neurogenesis. The studies of the regional localization of neurogenesis in the brain have been made possible due to several methods for detecting adult neurogenesis including; bromodeoxyuridine labeling (BrdU) together with markers of mature neurons, genetic labeling, by mouse transgenesis, or with the use of viral vectors. These techniques are already put to creative use and will be essential for the discovery of the nature of the adult neural stem cells. In this mini-review, we will discuss the localization of neural stem/progenitor cells in the brain and their implications as well as discussing the pro's and con's of stem cell labeling techniques.
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| 8. |
- Landgren, Henrik, 1978, et al.
(författare)
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Persistent FoxE3 expression blocks cytoskeletal remodeling and organelle degradation during lens fiber differentiation.
- 2008
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Ingår i: Investigative ophthalmology & visual science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783 .- 0146-0404. ; 49:10, s. 4269-77
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The anterior hemisphere of the lens is covered by an epithelial monolayer that acts as the stem cell population for lens fiber progenitors. Foxe3, a forkhead transcription factor, is essential for proliferation and survival of the epithelial cells, and cessation of Foxe3 expression at the lens equator coincides with the cell cycle arrest that marks initiation of fiber differentiation. In this study, the consequences of persistent Foxe3 expression during fiber differentiation was investigated. METHODS: The alpha-A-crystallin (Cryaa) promoter was used to drive transgenic expression of Foxe3 in murine differentiating lens fibers. RESULTS: Transgenic mice have a dramatically disturbed lens histology and grave cataracts. Microarray transcript profiling showed an increase of mRNAs normally enriched in epithelial cells, consistent with an epithelialization of the transgenic fibers. Some aspects of fiber differentiation were unaffected, such as the expression of alpha- and beta-crystallins and aquaporins, whereas cytoskeletal remodeling, cell adhesion, organelle degradation, and antimitotic signaling were compromised. CONCLUSIONS: Proper inactivation of FoxE3 expression at the lens equator is important for many aspects of fiber differentiation, and persistent expression leads to a partial epithelialization of fiber cells, with severe consequences for lens function.
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| 9. |
- Landgren, Sara, 1980, et al.
(författare)
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A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease
- 2012
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Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 119:7, s. 833-842
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid beta (A beta) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute A beta application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and A beta(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c) = 0.005; OR = 0.74; 95 % CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.
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| 10. |
- Landgren, Sara, 1980, et al.
(författare)
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Association of Pro-Ghrelin and GHS-R1A Gene Polymorphisms and Haplotypes With Heavy Alcohol Use and Body Mass.
- 2008
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Ingår i: Alcoholism, clinical and experimental research. - : Wiley. - 1530-0277 .- 0145-6008. ; 32:12, s. 2054-2061
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ghrelin, an orexigenic peptide, acts on growth hormone secretagogue receptors (GHS-R1A), expressed in the hypothalamus as well as in important reward nodes such as the ventral tegmental area. Interestingly, ghrelin has been found to activate an important part of the reward systems, i.e., the cholinergic-dopaminergic reward link. Additionally, the rewarding and neurochemical properties of alcohol are, at least in part, mediated via this reward link. There is comorbidity between alcohol dependence and eating disorders. Thus, plasma levels of ghrelin are altered in patients with addictive behaviors such as alcohol and nicotine dependence and in binge eating disorder. This overlap prompted as to investigate the pro-ghrelin and GHS-R1A genes in a haplotype analysis of heavy alcohol-using individuals. Methods: A total of 417 Spanish individuals (abstainers, moderate, and heavy alcohol drinkers) were investigated in a haplotype analysis of the pro-ghrelin and GHS-R1A genes. Tag SNPs were chosen using HapMap data and the Tagger and Haploview softwares. These SNPs were then genotyped using TaqMan Allelic Discrimination. Results: SNP rs2232165 of the GHS-R1A gene was associated with heavy alcohol consumption and SNP rs2948694 of the same gene as well as haplotypes of both the pro-ghrelin and the GHS-R1A genes were associated with body mass in heavy alcohol consuming individuals. Conclusions: The present findings are the first to disclose an association between the pro-ghrelin and GHS-R1A genes and heavy alcohol use, further strengthening the role of the ghrelin system in addictive behaviors and brain reward.
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