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PubMed2001

A novel human gene (SARM) at chromosome 17q11 encodes a protein with a SAM motif and structural similarity to Armadillo/beta-catenin that is conserved in mouse, Drosophila, and Caenorhabditis elegans.

A novel human gene, SARM, encodes the orthologue of a Drosophila protein (CG7915) and contains a unique combination of the sterile alpha (SAM) and the HEAT/Armadillo motifs. The SARM gene was identified on chromosome 17q11, between markers D17S783 and D17S841 on BAC clone AC002094, which also included a HERV repeat and keratin-18-like, MAC30, TNFAIP1, HSPC017, and vitronectin genes in addition to three unknown genes. The mouse SARM gene was located on a mouse chromosome 11 BAC clone (AC002324). The SARM gene is 1.8 kb centromeric to the vitronectin gene, and the two genes share a promoter region that directs a high level of liver-specific expression of both the SARM and the vitronectin genes. In addition to the liver, the SARM gene was highly expressed in the kidney. A 0.4-kb antisense transcript was coordinately expressed with the SARM gene in the kidney and liver, while in the brain and malignant cell lines, it appeared independent of SARM gene transcription. The SARM gene encodes a protein of 690 amino acids. Based on amino acid sequence homology, we have identified a SAM motif within this derived protein. Structure modeling and protein folding recognition studies confirmed the presence of alpha-alpha right-handed superhelix-like folds consistent with the structure of the Armadillo and HEAT repeats of the beta-catenin and importin protein families. Both motifs are known to be involved in protein-protein interactions promoting the formation of diverse protein complexes. We have identified the same conserved SAM/Armadillo motif combination in the mouse, Drosophila, and Caenorhabditis elegans SARM proteins.

Amino Acid Motifs↗
PubMed2001

Self-association studies on the EphB2 receptor SAM domain using analytical ultracentrifugation.

The self-association behavior of the Eph-kinases SAM domain has been studied in phosphate buffer, pH 7.4, containing 0.14 M NaCl using concentration-dependent sedimentation equilibrium experiments. Only weak interactions typical for a monomer-dimer equilibrium up to at least 12 mg/mL were observed. Such concentrated solutions require a consideration of the non-ideality expressed by virial coefficients. A special centrifuge equation was used for the global analysis to estimate equilibrium constants based on the thermodynamic activities of the reactants. When neglecting this, the parameters deviate by about 20%. Association constants for dimerization of the EphB2-SAM domain vary between 163 M(-1) at 10 degrees C and 395 M(-1) at 32 degrees C, indicating hydrophobic forces are involved in the dimerization process. In solutions of about 12 mg/mL, less than 50% dimers are in solution and higher oligomers can be excluded.

Amino Acid Motifs↗
PubMed1996

Beneficial effects of sigma agonists on the age-related learning impairment in the senescence-accelerated mouse (SAM).

A beneficial effect of sigma (sigma) agonists was previously described on several pharmacological models of learning impairments. We examined this effect in senescence-accelerated mice (SAM), which has been developed as a murine model of aging and cognitive dysfunction. SAMP8/Ta (P8, senescence-prone substrain), 10-12 months of age, showed significant impairments in mnemonic capacities, as compared to age-matched SAMR1/Ta controls (R1, senescence-resistant substrain). Tests included open-field behavior, spontaneous alternation performances in the Y-maze, step-down passive avoidance and place learning after repetitive training in a water-maze. Pretreatment with the sigma agonists JO-1784 (igmesine) or PRE-084, at 0.1-3 mg/kg, s.c., significantly improved spontaneous alternation and passive avoidance performances in P8. JO-1784 or PRE-084, at 1 mg/kg, also improved place learning in the water-maze, and retention, in term of escape latency. The implication of sigma sites was indicated by the lack of significant effect of JO-1783, the inactive enantiomer of JO-1784, and by the ability of BMY-14802 (5 mg/kg, i.p.) to antagonize the effects on passive avoidance of JO-1784 (0.5 mg/kg) or PRE-084 (1 mg/kg). Subchronic treatments with JO-1784 (0.5 mg/kg/day) or PRE-084 (1 mg/kg/day) during 10 days, allowed a significant improvement of learning during training in the water-maze, but retention was not significantly ameliorated. These results confirmed the interest of the SAM substrains as an experimental model for senile memory impairment and showed that sigma agonists could improve the quality of learning, although they seem less effective on long-term memory retrieval upon chronic administration.

Aging↗
PubMed1988

Cataract in senescence accelerated mouse (SAM). 2. Development of a new strain of mouse with late-appearing cataract.

A new strain of mouse with late-appearing hereditary cataract was developed in the Senescence Accelerated Mouse (SAM-R/3). At the beginning of the selection of the new strain (generation 4), 5% of mice which lived over 20 weeks had cataract, at least unilaterally. During selection and brother-sister inbreeding, the incidence increased and reached 68% of 78 mice whose lifespan exceeded 20 weeks, in the 12th generation. In recent populations, (generations 9-14), the cataract began to appear around 10 weeks of age and about 81% of 64 females and 49% of 47 males had cataract after 32 weeks of age. Inflammatory lesions of the cornea and eyelids began to occur later in life and the incidence was lower than that of cataract. This observation suggested to us that the cataract of this new strain was not congenital in origin but rather was age-related and did not occur consequently after the onset of inflammatory lesions around the lens tissue. Stereomicroscopic examination of the lens revealed that many of these cataracts occurred initially at the posterior area and that the mature cataract showed a characteristic protrusion at the posterior pole and nuclear dislocation. Histology of the mature cataract also revealed protrusion of the posterior pole and showed degeneration and liquefaction of lens cortex, nuclear dislocation and destruction of posterior lens capsule. The wet weight, water and protein contents showed that the lens of this strain developed normally and that the untoward events were the result but not the cause of cataract. The SAM-R/3 strain should prove to be a suitable murine model for investigation of age-related changes in the lens, and cataractogenesis.

Aging↗
PubMed1995

Age-related changes in learning and memory and cholinergic neuronal function in senescence accelerated mice (SAM).

The senescence-accelerated mouse (SAM) has been established as a murine model of accelerated aging. We investigated learning ability and memory in various tasks in a SAM strain, SAMP1TA, and in a control strain of SAMR1TA at the ages of 20, 30 and 40 weeks. We also measured choline acetyltransferase (ChAT) and cholinesterase (ChE) activity in the brains of these mice at the same ages. In a Y-maze task, in which short-term memory can be examined, there was no difference in learning ability between SAMP1TA and SAMR1TA at any age. Ability in latent learning and passive-avoidance tasks was less in SAMP1TA at 30 weeks of age than in age-matched SAMR1TA. The level of ChAT activity in the striatum of SAMP1TA was lower, than that of SAMR1TA at the ages of 20 and 30 weeks. At the ages of 40 and 50 weeks, ChE activity in the striatum of SAMP1TA was lower than that of SAMR1TA. These results suggest that SAMP1TA has a deficit, with cholinergic neuronal dysfunction, in learning ability and memory, as shown by impairment of performance in latent learning and long-term memory, but not in short-term memory.

Aging↗
PubMedDate not supplied

Age-related changes in footshock avoidance acquisition and retention in senescence accelerated mouse (SAM).

An inbred strain has been developed which exhibits some characteristics of aging in mice as young 6 months of age. The strain was designated "Senescence Accelerated Mouse" (SAM). A subline of the SAM strain, P/8, has an early onset of impaired learning in appetitive and aversive training tasks. Simple aversive and appetitive tasks were learned normally up to 12 months of age, whereas more difficult tasks detected impairment as early as 6 months of age while the mice still had good general health. Comparable impairment of learning and memory in C57BL/6Nnia mice was not detected until about 24 months of age which is near the end of the strain's lifespan when general health declines. In the present study, we report age-dependent impairment of acquisition and retention for footshock avoidance conditioning. Long-term (1 week) but not short-term (1 h) retention was adversely effected by aging. In 12-month-old P/8 mice, practicing the avoidance response (overtraining) did not alleviate the impairment of long-term memory processing.

Aging↗
PubMed1994

Brain ATP:L-methionine S-adenosyltransferase (MAT), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH): regional distribution and age-related changes.

The distribution of the activity of the enzyme methionine adenosyltransferase (ATP:L-methionine S-adenosyltransferase, EC 2.5.1.6, MAT) was investigated in human postmortem brains of individuals without a known history of neuropsychiatric disorders. The brain regions were the frontal, temporal, parietal and occipital cortices, nucleus caudatus, putamen, globus pallidus, thalamus and white matter. The activities in the nucleus caudatus and putamen were approximately 25% higher than the activities in the seven other brain regions, however, not on a statistically significant level. The apparent values of MAT Km and Vmax in the parietal cortex were 11.41 +/- 3.51 microM methionine and 25.72 +/- 3.90 nmol/mg protein/h, respectively. In the frontal cortex, a significant positive correlation between age and the activity of MAT was found (r = 0.997, P < 0.01). Concerning MAT stability in the rat brain, there was a steady decrease in the activity with postmortem time in the brains kept for 0-72 h at room temperature (23 degrees C), which reached the level of significance at 24 h. The activity did not change significantly when the brains were kept for 120 h at 4 degrees C, or by freezing and thawing the tissue before analysis. In a parallel study in rats of different ages (2-22 months), a homogeneous distribution of SAM and SAH was observed in the cortex, striatum, midbrain, hypothalamus, brainstem and cerebellum. The lowest levels of SAM and the highest levels of SAH observed in the striatum gave the lowest SAM/SAH ratio. The SAH content of rat cerebral cortex was highest in the oldest group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2006

[Lasting treatment of facial HIV and non HIV lipoatrophies through the use of SAM GoreTex malar implants and polyacrylamide hydrogel filler Eutrophill. About 90 consecutive cases].

HIV-related lipoatrophy (HIV LA) stands out with regard to its recent discovery, increasing incidence, multiple etiologies, relatively low morbidity, apparently irreversible effects, and unequivocal clinical features. The underlying cause of HIVLA is still controversial but there is an increasing demand of correction. We describe a technique using soft malar implants and acrylamid gel injections separately or in combination. Expanded polytetrafluoroethylene (Gore SAM) malar implants are used for augmentation of the most sunken areas below the eye; they should be placed subperiostealy and more medially than conventional implants. After trying sheets and custom made implants, preshaped GoreTex) Sam implants are now used systematicaly. Eutrophill) is a 2.5% polyacrylamide hydrogel obtained by polymerization of acrylamide monomers with an official half-life of 5 years. The soluable chains are more or less slowly released by enzymatic degradation and subsequently cleared via interstitial tissue without further metabolism or degradation. Injection should be performed continuously and evenly from one side to the other in the deepest part of the sunken area at the subcutaneous level only. A total of 90 consecutive patients were treated using implants alone in 11 cases, injections alone in 68 cases, and both implants and injections in 11 cases. Drawbacks were very few except three cases of chronic inflammation (dental conflict) with sheets and custom made implants which were never observed since the use of preshaped forms, and some very light bulgings with acrylamid injections which usually desapear in a few months. Mean follow-up was 17 months for injections and 29 for implants.

Acrylic Resins↗
PubMed2006

Glutamate 2,3-aminomutase: a new member of the radical SAM superfamily of enzymes.

A gene eam in Clostridium difficile encodes a protein that is homologous to lysine 2,3-aminomutase (LAM) in many other species but does not have the lysyl-binding residues Asp293 and Asp330 in LAM from Clostridium subterminale SB4. The C. difficile protein has Lys and Asn, respectively, in the sequence positions of the essential Asp residues in LAM. The C. difficile gene has been cloned into an E. coli expression vector, expressed in E. coli, and the protein purified and characterized. The recombinant protein displays excellent activity as a glutamate 2,3-aminomutase and no activity toward l-lysine. The PLP-, iron-, and sulfide-content and ultraviolet/visible spectrum are similar to LAM, and the enzyme requires SAM and dithionite as activators, as does LAM. Freeze-quench EPR experiments in the presence of l-glutamate reveal a glutamate-based free radical in the steady state of the reaction. A number of other bacterial genomes include genes encoding proteins homologous to the glutamate 2,3-aminomutase from C. difficile, and four of these proteins display the activity of glutamate 2,3-aminomutase when produced in E. coli. All of the homologous proteins have the cysteine motif CSMYCRHC corresponding to the motif CxxxCxxC characteristic of radical SAM enzymes. It is concluded that glutamate 2,3-aminomutase from C. difficile is a representative of a family found in a number of bacteria. It is likely that the beta-glutamate found in a few bacterial and archeal species as an osmolyte arises from the action of glutamate 2,3-aminomutase.

Amino Acid Sequence↗
PubMed2006

Immobilization of Protein A on SAMs for the elaboration of immunosensors.

Binary mixtures of 11-mercaptoundecanoic acid (MUA) and other thiols of various lengths and terminal functions were chemisorbed on gold-coated surfaces via S-Au bonds to form mixed self-assembled monolayers (SAMs). Several values of the mole fraction of MUA in the thiol mixtures were tested and the structure and composition of the resulted thin films were characterized by X-ray photoelectron spectroscopy (XPS) and polarization modulation infrared reflection-absorption spectroscopy (PM-IRRAS). The results made it clear that co-adsorption of MUA with thiols of similar chain length led to well-ordered monolayers whereas the co-adsorption of MUA with shorter thiols yielded less crystalline-like thin films, but with more reactive carboxylic acid terminal groups. This criterion appeared decisive for efficient covalent binding of Staphylococcus aureus Protein A (PrA), a protein that displays high affinity for the constant fragment (Fc) of antibodies of the IgG type from various mammal species. The ability of immobilized Protein A to recognize and bind a model IgG appeared to be optimal for the mixed SAM of MUA and the short-chain, omega-hydroxythiol 6-mercaptohexanol in the proportion 1-3.

Fatty Acids↗
PubMed2005

Systolic anterior motion (SAM) of the posterior mitral leaflet: left ventricular outflow tract obstruction in a patient without left ventricular hypertrophy.

Systolic anterior motion (SAM) of the anterior mitral leaflet with mitral-septal contact was generally thought to be a major contributor to dynamic left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. We report an interesting case of SAM of the posterior mitral leaflet in a patient without left ventricular hypertrophy, which led to dynamic left ventricular obstruction.

Aged↗
PubMed2000

Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8.

The senescence-accelerated mouse (SAM) is known to be a murine model for accelerated aging. The SAMP8 strain shows age-related deterioration of learning and memory at an earlier age than control mice (SAMR1). In the present study, we investigated the changes in expressions of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the brain of SAMP8. In the hippocampus of 10 months old SAMP8, the expression of IL-1 mRNA was significantly elevated in comparison with that of SAMR1. In both strains of SAMs, increases in IL-1beta protein in the brain were observed at 10 months of age compared with 2 and 5 months. The only differences found between the strain in protein levels were at 10 months and were elevations in IL-1beta in the hippocampus and hypothalamus, and in TNF-alpha and IL-6 in the cerebral cortex and the hippocampus in SAMP8 as compared with SAMR1. However, lipopolysaccharide-induced increases in the expression of these cytokines in brain did not differ between SAMP8 and SAMR1. Increases in expression of proinflammatory cytokines in the brain may be involved in the age-related neural dysfunction and/or learning deficiency in SAMP8.

Aging↗
PubMed1997

Differences between the circadian system of two strains of senescence-accelerated mice (SAM).

The aim of this study was to look for morphological or functional differences between the circadian system of two substrains of Senescence Accelerated Mice (SAM): senescence-prone (SAMP8; average median survival time = 10.0 months) and senescence-resistant (SAMR1; average median survival time = 18.9 months). Neither the general structure nor the quantitative analysis of the number of VP-positive neurons in matched sections revealed differences between SAMP8 and SAMR1 mice. Under LD 12/12 photoperiod, all animals showed the typical pattern of wheel running activity with maximum activity in the first half of darkness period. The period of the locomotor activity in free running as well as the time course for synchronization after a 6 h phase delay of LD cycle were similar in both strains of SAM mice. However, SAMP8 animals reentrained significantly earlier (3.4 +/- 0.4 days) than SAMR1 (6.3 +/- 0.9 days) after a 6 h phase advance of LD cycle. We conclude that the circadian system of SAMP8 mice presents some functional differences with that of SAMR1, which could help to explain their different rate of ageing.

Aging↗
PubMed2000

Age-related changes in myelopoietic response to lipopolysaccharide in senescence-accelerated (SAM) mice.

The effects of in vivo lipopolysaccharide (LPS) administration on myelopoiesis were examined in senescence-accelerated (SAM) mice. Young mice injected with LPS exhibited: (a) increased femoral proliferative pool size; (b) transient reduction in femoral non-proliferative pool size and number of femoral colony forming unit-granulocyte macrophages (CFU-GMs); (c) marked increase in splenic CFU-GMs; and (d) transient increase in S-phase of femoral CFU-GMs. The responses of old mice after LPS administration differed from those of young mice in the following points: (a) no recovery of the femoral non-proliferative pool or femoral CFU-GMs, (b) less significant augmentation of the femoral proliferative pool and splenic CFU-GMs, and (c) prolonged reduction in S-phase of femoral CFU-GM. Injection of LPS into mice resulted in a hyperproduction of colony-stimulating activity (CSA) in bone followed by production of colony-inhibitory activity (CIA) in young mice and in contrast, an excessive CIA secretion from bone without an increase in CSA levels in old mice. These imbalances in the regulatory factors derived from non-hemopoietic cells in the bones may lead to an inappropriate response of myelopoiesis in aged SAM mice after LPS administration, which may play a key role in infections.

Aging↗
PubMed2001

Comparison of the lateral diffusion coefficient of hepatocyte plasma membrane proteins in three strains of sensescence accelerated mouse (SAM).

The lateral diffusion coefficients of proteins (D(p)) were measured in hepatocyte plasma membrane in freshly prepared liver smears by means of the fluorescence recovery after photobleaching (FRAP) method. D(p) was measured after development of peroxide-induced autofluorescence (PIAF) in a total of 115 senescence accelerated mice (SAM), distributed in three strains, at least five age-groups in each, as follows: (i) SAMR1TA (25 males and 22 females), medium life span (MLS) in months, under specific pathogen free (SPF) conditions, MLS(spf) 20.1 and 20.0, respectively, while under conventional conditions, MLS(Deltapf)=18.9 in average for both sexes; (ii) SAMP6/Ta (18 males and 17 females), MLS(spf)=17.1 and 15.3, respectively, and MLS(cc)=8.1 for both sexes; (iii) SAMP6/Ta (17 males and 16 females), MLS(spf)=15.6 and 14.7, respectively, and MLS(cc)=10.0 for both sexes. A highly significant negative linear age-correlation of D(p) (R=0.975 or higher) was found in each strain, being roughly proportional with the MLS(cc) values. Since the studied mice kept under SPF conditions survived longer, than under conventional conditions, the actual age-dependent decay rates of D(p) values did not differ significantly in two pairs of comparisons (female R1/P6 and female R1/P8), whereas they did in all other possible pairs, including also the normal C57BL/6 mice. The main conclusion can be drawn that the D(p) of hepatocyte membranes is a good biomarker of aging and survival also in SAM, as in all other inbred and outbred rodents, studied so far.

Journal Article↗
PubMed1998

Imbalances in N-CAM, SAM and polysialic acid may underlie the paranodal ion channel barrier defect in diabetic neuropathy.

Breakdown of protective tissue barrier systems characterizes the chronic diabetic complications affecting the retina, and peripheral and central nerve tracts. The progressive damages to the blood-retina-, blood-nerve-, and paranodal ion channel barriers have pathophysiological consequences for the relentless progression of these complications. The continuing damage to the paranodal ion channel barrier in the spontaneously diabetic BB/W rat is associated with an increasingly irreversible nerve conduction defect, due to impaired nodal Na+ currents associated with displacement of nodal Na+ channels across the damaged paranodal barrier. The structural substrate for the mechanical barrier of the paranode is provided by electron-dense junctional complexes made up by a moiety of neural cell adhesive-(N-CAM), neural-glial adhesive (Ng-CAM), substrate adhesive molecules (SAMs) and polysialic acid (PSA). To further explore the mechanism underlying the protective barrier defect in diabetic neuropathy we examined the expression and immunolocalization of these molecules in peripheral nerve. In 6-month diabetic BB/W rats, direct and indirect ELISAs revealed significantly up-regulated N-CAM (P < 0.05), tenascin (Ng-CAM), (P < 0.001) and N-cadherin (A-CAM) (P < 0.03). On the other hand, SAMs showed little change, except for PSA which showed a significantly (P < 0.03) decreased concentration in the diabetic nerve. Immunocytochemical identification of these molecules revealed no visually detectable differences between diabetic and control rats. In conclusion, these data suggest that imbalances between highly interactive molecules responsible for the adhesiveness between terminal Schwann cell loops and the paranodal axolemma may underlie the critical paranodal barrier defect in diabetic neuropathy.

Animals↗
PubMedDate not supplied

Aging of blood-brain barrier and neuronal cells of eye and ear in SAM mice.

The SAMP, Senescence-Accelerated Mouse strains show senescence acceleration and age-associated pathological phenotypes similar to geriatric disorders seen in humans. Among these strains, SAMP8 mice show age-associated deficits in learning and memory. Histopathological studies revealed various neurodegenerative changes in the brain, including age-associated appearance of spongiform degeneration in the brain stem and of PAS-positive granular structures in the hippocampus. The blood-brain barrier (BBB) function of SAMP8 mice was also impaired with advancing age. The compromised BBB function in the olfactory bulb, the hippocampus and the pons of SAMP8 mice coincided with and might have been the cause of some morphological changes. Age-associated degeneration of receptor cells and ganglion neurons in the retina and cochlea also occurred in the SAM mice. Oxidative stress partly caused by mitochondrial dysfunction was detected and may be a cause of the neuronal cell degeneration. The SAM strains are useful tool in the attempt to understand the mechanisms of age-dependent neurodegeneration and to develop clinical interventions.

Aging↗
PubMed1998

An avian cDNA encoding a tyrosine-phosphorylated protein with PDZ, coiled-coil, and SAM domains.

Tyrosine phosphoproteins of size 115-120 kDa were purified from membranes of chicken embryo fibroblasts (CEF) infected with Rous sarcoma virus (RSV). A mouse was immunized with these proteins, and the immune serum was used to screen a CEF cDNA expression library. A highly immunoreactive clone (KS5) was identified and characterized. The cDNA of this clone is 2.3 kb in length with a short 5' UTR and a single major open reading frame (ORF) encoding a polypeptide of 719 amino acids, with a calculated molecular weight of 81.1 kDa. The encoded protein contains an amino terminal PDZ domain, followed by a predicted coiled-coil region, a PEST domain, and a carboxy-terminal SAM domain. Consensus sequence motifs for tyrosine phosphorylation are also present, as are consensus sequences for the binding of SH2 and PDZ domains. Antisera from mice immunized with bacterially expressed fragments of the KS5 protein recognized proteins of size 230, 116, and 65 kDa in CEF. In other chicken embryo tissues, a 116-kDa species was the predominant protein recognized. The 116-kDa species is tyrosine-phosphorylated in RSV-CEF. The presence of PDZ and SAM domains in the KS5 protein suggests that it may act as a molecular adaptor, promoting and relaying information in a signal transduction pathway. It is a member of a family of related proteins, all of which have a highly conserved PDZ domain adjacent to a coiled-coil region. Two other members of this family are the neuronal proteins spinophilin (Allen, P.B., Ouimet, C.C., Greengard, P., 1997. Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. Proc. Natl. Acad. Sci. USA 94, 9956-9961) and neurabin (Nakanishi, H., Obaishi, H., Satoh, A., Wada, M., Mandai, K., Satoh, K., Nishioka, H., Matsuura, Y., Mizoguchi, A. , Takai, Y., 1997. Neurabin: A novel neural tissue-specific actin filament-binding protein involved in neurite formation. J. Cell Biol. 139, 951-961).

Alternative Splicing↗