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Biomedical subjects

Leena Peltonen

Publications and source records attributed to Leena Peltonen.

At least 19 recordsLinked to original sources
PubMed2005

Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons.

Infantile Neuronal Ceroid Lipofuscinosis (INCL) results from mutations in the palmitoyl protein thioesterase (PPT1, CLN1) gene and is characterized by dramatic death of cortical neurons. We generated Ppt1Deltaex4 mice by a targeted deletion of exon 4 of the mouse Ppt1 gene. Similar to the clinical phenotype, the homozygous mutants show loss of vision from the age of 8 weeks, seizures after 4 months and paralysis of hind limbs at the age of 5 months. Autopsy revealed a dramatic loss of brain mass and histopathology demonstrated accumulation of autofluorescent granular osmiophilic deposits (GRODS), both characteristic of INCL. At 6 months, the homozygous Ppt1Deltaex4 mice showed a prominent loss of GABAergic interneurons in several brain areas. The transcript profiles of wild-type and mutant mouse brains revealed that most prominent alterations involved parts of the immune response, implicating alterations similar to those of the aging brain and neurodegeneration. These findings make the Ppt1Deltaex4 mouse an interesting model for the inflammation-associated death of interneurons.

Animals↗
PubMed2005

Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a recessively inherited disease characterized by early onset dementia associated with bone cysts. Our group has recently established the molecular background of PLOSL by identifying mutations in DAP12 and TREM2 genes. To understand how loss of function of the immune cell activating DAP12/TREM2 signaling complex leads to dementia and loss of myelin, we have analyzed here Dap12 and Trem2 expression in the mouse CNS. We show that Dap12 and Trem2 are expressed from embryonic stage to adulthood, and demonstrate a highly similar expression pattern. In addition, we identify microglial cells and oligodendrocytes as the major Dap12/Trem2-producing cells in the CNS and, consequently, as the predominant cell types involved in PLOSL pathogenesis. These findings provide a good starting point for the study of the molecular mechanisms of this inherited dementia and new evidence for the involvement of the immune system in neuronal degeneration.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Family-based association study of DYX1C1 variants in autism.

DYX1C1: was recently identified as a candidate gene for developmental dyslexia, which is characterized by an unexpected difficulty in learning to read and write despite adequate intelligence, motivation, and education. It will be important to clarify, whether the phenotype caused by DYX1C1 extends to other language-related or comorbid disorders. Impaired language development is one of the essential features in autism. Therefore, we analyzed the allelic distribution of the DYX1C1 gene by family-based association method in 100 Finnish autism families. No evidence for association was observed with any intragenic marker or with haplotypes constructed from alleles of several adjacent markers. No evidence for deviated allelic diversity was either observed: the frequency of expected dyslexia risk haplotype was comparable to its frequency in Finnish controls. Thus it seems unlikely that DYX1C1 gene would be involved in the genetic etiology of autism in Finnish patients.

Alleles↗
PubMed2004

Gene dosage--limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity.

Inactivation of the autoimmune regulator (Aire) gene causes a rare recessive disorder, autoimmune polyendocrine syndrome 1 (APS1), but it is not known if Aire-dependent tolerance mechanisms are susceptible to the quantitative genetic changes thought to underlie more common autoimmune diseases. In mice with a targeted mutation, complete loss of Aire abolished expression of an insulin promoter transgene in thymic epithelium, but had no effect in pancreatic islets or the testes. Loss of one copy of Aire diminished thymic expression of the endogenous insulin gene and the transgene, resulting in a 300% increase in islet-reactive CD4 T cells escaping thymic deletion in T cell receptor transgenic mice, and dramatically increased progression to diabetes. Thymic deletion induced by antigen under control of the thyroglobulin promoter was abolished in Aire homozygotes and less efficient in heterozygotes, providing an explanation for thyroid autoimmunity in APS1. In contrast, Aire deficiency had no effect on thymic deletion to antigen controlled by a systemic H-2K promoter. The sensitivity of Aire-dependent thymic deletion to small reductions in function makes this pathway a prime candidate for more subtle autoimmune quantitative trait loci, and suggests that methods to increase Aire activity would be a potent strategy to lower the incidence of organ-specific autoimmunity.

Animals↗
PubMed2004

A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging.

Neuronal ceroid lipofuscinoses (NCL) comprise the most common group of childhood encephalopathies caused by mutations in eight genetic loci, CLN1-CLN8. Here, we have developed a novel mouse model for the human vLINCL (CLN5) by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5-/- mice showed loss of vision and accumulation of autofluorescent storage material in the central nervous system (CNS) and peripheral tissues without prominent brain atrophy. The ultrastructure of the storage material accurately replicated the abnormalities in human patients revealing mixture of lamellar profiles including fingerprint profiles as well as curvilinear and rectilinear bodies in electronmicroscopic analysis. Prominent loss of a subset of GABAergic interneurons in several brain areas was seen in the Cln5-/- mice. Transcript profiling of the brains of the Cln5-/- mice revealed altered expression in several genes involved in neurodegeneration, as well as in defense and immune response, typical of age-associated changes in the CNS. Downregulation of structural components of myelin was detected and this agrees well with the hypomyelination seen in the human vLINCL patients. In general, the progressive pathology of the Cln5-/- brain mimics the symptoms of the corresponding neurodegenerative disorder in man. Since the Cln5-/- mice do not exhibit significant brain atrophy, these mice could serve as models for studies on molecular processes associated with advanced aging.

Aging↗
PubMed2004

Nanoparticles containing ketoprofen and acrylic polymers prepared by an aerosol flow reactor method.

The purpose of this study was to outline the effects of interactions between a model drug and various acrylic polymers on the physical properties of nanoparticles prepared by an aerosol flow reactor method. The amount of model drug, ketoprofen, in the nanoparticles was varied, and the nanoparticles were analyzed for particle size distribution, particle morphology, thermal properties, IR spectroscopy, and drug release. The nanoparticles produced were spherical, amorphous, and had a matrix-type structure. Ketoprofen crystallization was observed when the amount of drug in Eudragit L nanoparticles was more than 33% (wt/wt). For Eudragit E and Eudragit RS nanoparticles, the drug acted as an effective plasticizer resulting in lowering of the glass transition of the polymer. Two factors affected the preparation of nanoparticles by the aerosol flow reactor method, namely, the solubility of the drug in the polymer matrix and the thermal properties of the resulting drug-polymer matrix.

Aerosols↗
PubMed2004

Locus for quantitative HDL-cholesterol on chromosome 10q in Finnish families with dyslipidemia.

Decreased HDL-cholesterol (HDL-C) and familial combined hyperlipidemia (FCHL) are the two most common familial dyslipidemias predisposing to premature coronary heart disease (CHD). These dyslipidemias share many phenotypic features, suggesting a partially overlapping molecular pathogenesis. This was supported by our previous pooled data analysis of the genome scans for low HDL-C and FCHL, which identified three shared chromosomal regions for a qualitative HDL-C trait on 8q23.1, 16q23.3, and 20q13.32. This study further investigates these regions as well as two other loci we identified earlier for premature CHD on 2q31 and Xq24 and a locus for high serum triglycerides (TGs) on 10q11. We analyzed 67 microsatellite markers in an extended study sample of 1,109 individuals from 92 low HDL-C or FCHL families using both qualitative and quantitative lipid phenotypes. These analyses provided evidence for linkage (a logarithm of odds score of 3.2) on 10q11 using a quantitative HDL-C trait. Importantly, this region, previously linked to TGs, body mass index, and obesity, provided evidence for association for quantitative TGs (P = 0.0006) and for a combined trait of HDL-C and TGs (P = 0.008) with marker D10S546. Suggestive evidence for linkage also emerged for HDL-C on 2q31 and for TGs on 20q13.32. Finnish families ascertained for dyslipidemias thus suggest that 10q11, 2q31, and 20q13.32 harbor loci for HDL-C and TGs.

Adult↗
PubMed2004

Segmental duplications flank the multiple sclerosis locus on chromosome 17q.

Large chromosomal rearrangements, duplications, and inversions are relatively common in mammalian genomes. Here we report interesting features of DNA strands flanking a Multiple Sclerosis (MS) susceptibility locus on Chromosome 17q24. During the positional cloning process of this 3-Mb locus, several markers showed a radiation hybrid clone retention rate above the average (1.8-fold), suggestive for the existence of duplicated sequences in this region. FISH studies demonstrated multiple signals with three of the tested regional BACs, and 24 BACs out of 187 showed evidence for duplication in shotgun sequence comparisons of the 17q22-q24 region. Specifically, the MS haplotype region proved to be flanked by palindromic sequence stretches and by long segmental intrachromosomal duplications in which highly homologous DNA sequences (>96% identity) are present at both ends of the haplotype. Moreover, the 3-Mb DNA segment, flanked by the duplications, is inverted in the mouse genome when compared with the orientation in human and chimp. The segmental duplication architecture surrounding the MS locus raises the possibility that a nonallelic homologous recombination between duplications could affect the biological activity of the regional genes, perhaps even contributing to the genetic background of MS.

Animals↗
PubMed2004

Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q.

Research to identify predisposing genes for complex diseases relying solely on clinical diagnosis is probably not ideal. Here, we analyzed genome-wide data for 168 schizophrenia families using neuropsychological variables associated with disease susceptibility, with the aid of SOLAR, a program for variance-component analysis. The linkage signal was greatly accentuated by application of the quantitative traits compared with diagnosis. We found evidence for a locus for verbal learning and memory on 4q21 (Z=3.01, Z(mp)=3.84 and empiric P=0.031 for delayed memory; Z=2.96, Z(mp)=3.4 and P=0.026 for verbal learning) and suggestive evidence for visual working memory on 2q36 (Z=2.80, Z(mp)=2.08 and P=0.093). In addition, some evidence emerged for a locus for recognition memory on 10p13, visual attention on 15q22 and executive function on 9p22 in the complete sample, as well as for delayed memory on 8q12, semantic clustering and intrusions on 1q42 and visual attention on 3p25 in the genealogically distinctive sample subsets. Of the loci linked to schizophrenia in diverse populations, in addition to the earlier mentioned regions, some evidence of linkage was observed for 2q, 6q, 7q, 11q, 13q, 14q, 18q and 22q. Our results reveal initial information on the effect of the loci associated with schizophrenia in multiple studies, and emphasize the value of trait components in the search for susceptibility loci for complex diseases.

Analysis of Variance↗
PubMed2004

Improved entrapment efficiency of hydrophilic drug substance during nanoprecipitation of poly(l)lactide nanoparticles.

The purpose of this research was to improve the entrapment efficiency of a model hydrophilic drug substance, sodium cromoglycate, loaded inside polylactic acid nanoparticles by a modified nanoprecipitation method. The effect of formulation parameters was studied to improve the entrapment efficiency of the drug substance inside the nanoparticles. Several parameters (changes in the amount of model drug, solvent selection, electrolyte addition, pH alteration) were tested in order to increase the loading of the hydrophilic drug in the hydrophobic nanoparticles. Lowering of the pH was the most efficient way to increase the drug loading; up to approximately 70% of the sodium cromoglycate used in the particle formation process could be loaded inside the particles. The loading efficiency without the pH change was around 10% to 15% at maximum. The crystallinity values and crystal habits of the sodium cromoglycate nanoparticles were studied (x-ray diffraction) before and after the lowering of the pH. The change in pH conditions during the nanoprecipitation process did not affect markedly the crystallinity properties of the drug substance. According to this study, it is possible to improve the entrapment efficiency of hydrophilic sodium cromoglycate inside of the nanoparticles by small changes in the process parameters without alterations in the physical properties of the original drug substance.

Chemical Precipitation↗
PubMed2004

Autoproteolytic activation of human aspartylglucosaminidase.

Aspartylglucosaminidase (AGA) belongs to the N-terminal nucleophile (Ntn) hydrolase superfamily characterized by an N-terminal nucleophile as the catalytic residue. Three-dimensional structures of the Ntn hydrolases reveal a common folding pattern and equivalent stereochemistry at the active site. The activation of the precursor polypeptide occurs autocatalytically, and for some amidohydrolases of prokaryotes, the precursor structure is known and activation mechanisms are suggested. In humans, the deficient AGA activity results in a lysosomal storage disease, aspartylglucosaminuria (AGU) resulting in progressive neurodegeneration. Most of the disease-causing mutations lead to defective molecular maturation of AGA, and, to understand the structure-function relationship better, in the present study, we have analysed the effects of targeted amino acid substitutions on the activation process of human AGA. We have evaluated the effect of the previously published mutations and, in addition, nine novel mutations were generated. We could identify one novel amino acid, Gly258, with an important structural role on the autocatalytic activation of human AGA, and present the molecular mechanism for the autoproteolytic activation of the eukaryotic enzyme. Based on the results of the present study, and by comparing the available information on the activation of the Ntn-hydrolases, the autocatalytic processes of the prokaryotic and eukaryotic enzymes share common features. First, the critical nucleophile functions both as the catalytic and autocatalytic residue; secondly, the side chain of this nucleophile is oriented towards the scissile peptide bond; thirdly, conformational strain exists in the precursor at the cleavage site; finally, water molecules are utilized in the activation process.

Amino Acids↗
PubMed2004

Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1).

Familial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both, is observed in about 20% of individuals with premature coronary heart disease. We previously identified a locus linked to FCHL on 1q21-q23 in Finnish families with the disease. This region has also been linked to FCHL in families from other populations as well as to type 2 diabetes mellitus. These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies combined hyperlipidemia in mice, is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism.

Animals↗
PubMed2004

Seasonal affective disorder and the G-protein beta-3-subunit C825T polymorphism.

BACKGROUND: Guanine nucleotide-binding proteins (G-proteins) have been implicated in affective disorders, with reports of altered signal transduction and G-protein levels. Association with seasonal affective disorder (SAD) has been found for the higher activity T-allele of the G-protein beta-3-subunit C825T polymorphism. METHODS: European SAD patients (n = 159) and matched controls (n = 159) were genotyped for the C825T. Seasonality and diurnal preference were investigated in subsets of the material (n = 177 and 92, respectively). RESULTS: We found no association between C825T and SAD (chi(2) =.09, p =.96) or seasonality (F = 1.76, p =.18). There was some evidence for an effect on diurnal preference but only in the control group (n = 46, t = -2.8, Bonferroni corrected p =.045). CONCLUSIONS: These results suggest that the G-protein beta-3-subunit 825 T-allele does not play a major role in susceptibility to seasonal affective disorder in the population studied.

Alleles↗
PubMed2004

Formation and characterization of three-component-sorbitan monoester surfactant, oil and water-creams.

The effect of molecular structure of four sorbitan monoester surfactants (sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate and sorbitan monooleate) on the formation of simple three-component creams is presented. Interfacial properties of the surfactants were determined using a du Nouy tensiometer and rheological properties of selected creams with oscillation stress sweep, creep recovery and viscosity tests. Depending on the composition, sorbitan monolaurate and sorbitan monooleate formed both o/w creams and w/o creams, while sorbitan monopalmitate and sorbitan monostearate formed only o/w creams. Sorbitan monostearate and sorbitan monopalmitate had the smallest cmc and A(cmc) values and they were the most effective surfactants in lowering the interfacial tension. These surfactants formed the most stable and elastic creams with clear linear viscoelastic regions and small compliance values. Sorbitan monolaurate and sorbitan monooleate formed viscous creams without elastic properties.

Drug Compounding↗
PubMed2004

A novel aspartylglucosaminuria mutation affects translocation of aspartylglucosaminidase.

The AGA gene is mutated in patients with aspartylglucosaminuria (AGU), a lysosomal storage disease enriched in the Finnish population. The disease mechanism of AGU and the biochemistry and cell biology of the lysosomal aspartylglucosaminidase (AGA) enzyme are well characterized. Here, we have investigated a novel AGU mutation found in a Finnish patient. The mutation was detected as a compound heterozygote with the Finnish major mutation in the other allele. The novel point mutation, c.44T>G, causes the L15R amino acid substitution in the signal sequence of the AGA enzyme. The mutated AGA enzyme was here analyzed by over expression in BHK and COS-1 cells. The L15R AGA protein was only faintly detectable by immunofluorescence analysis and observed in the endoplasmic reticulum. Metabolic labeling and immunoprecipitation revealed only a small amount of AGA polypeptides but the specific activity of the mutant enzyme was surprisingly high, 37% of the wild type. The amino acid substitution probably affects translocation of AGA polypeptides by altering a critical hydrophobic core structure of the signal sequence. It appears that the small amounts of active enzyme are not able to reach the lysosomes thus explaining the development of AGU disease in the patient.

Amino Acid Sequence↗
PubMed2004

Comparative physical maps of the human and mouse Meckel syndrome critical regions.

Meckel syndrome (MKS-OMIM 24900) is an autosomal recessive disease characterized by cystic kidneys, occipital encephalocele, polydactyly, and fibrotic changes of the liver, typically resulting in postnatal death. A Meckel syndrome critical region (MKS1) maps to human Chromosome (Chr) 17, in a region of homology to mouse Chr 11. Here we report the comparison of human Chr 17q23 with mouse Chr 11. We have generated physical maps of the human and mouse MKS1 critical regions. Additionally, we have created a transcript map of the MKS1 critical region in both species. By comparing these physical maps, we observe a high degree of similarity in gene order in the human and mouse Meckel syndrome critical regions. We have also examined the expression patterns of genes in the MKS1 region to assess their potential as MKS1 candidates. Finally, we have analyzed genes present in the other Meckel syndrome critical regions, MKS2 and MKS3, to determine whether any of the candidate genes for the three MKS loci have similar gene functions or are members of a common biological pathway.

Abnormalities, Multiple↗
PubMed2004

Isolates and their potential use in complex gene mapping efforts.

Linkage disequilibrium (LD), detectable with microsatellites in disease alleles over wide genetic intervals in population isolates, has facilitated mapping and positional cloning of numerous disease genes. We, among others, have shown that the LD intervals reach up to 1 Mb in general alleles of young subisolates, and that this feature most probably offers an avenue for the initial locus positioning for complex traits. Development of efficient SNP genotyping and characterization of haploblock structure of the human genome have introduced new prospects to LD-based fine mapping and haplotype-association studies. Encouraging associations have been reported for several complex diseases. Final breakthroughs in mapping of complex disease loci have emerged on large pedigrees in population isolates. Conversely, ignoring genealogical makeup of the study population seems to disclose false negative and false positive associations, directing resources down the drain.

Chromosome Mapping↗