Lack of functional messenger RNA (mRNA) coding for a microtubule-associated protein correlates with poor performance of rats in a behavioral paradigm.
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Animals↗
Biomedical subjects
G S Zubenko
Publications and source records attributed to G S Zubenko.
Mutations in PEP4 locus of Saccharomyces cerevisiae block final step in maturation of two vacuolar hydrolases.
The biosynthesis of carboxypeptidase Y (EC 3.4.16.1) and proteinase A (EC 3.4.23.6) in yeast cells involves a series of posttranslational events, the last of which is dependent upon a function supplied by the PEP4 gene. Because pep4 mutations result in a 90-95% reduction in the levels of activity of at least three additional vacuolar hydrolases, it is likely that these, and perhaps all, yeast vacuolar hydrolases are synthesized as inactive precursors, which mature by a common mechanism that depends upon a function supplied by the PEP4 gene. The pep4 mutation shows an apparent gene dosage effect on levels of activity of proteinases A and B but not on the level of activity of carboxypeptidase Y. This effect appears to come about because the maturation machinery is capable of discriminating among these hydrolase precursors.
Aspartic Acid Endopeptidases↗
PEP4 gene function is required for expression of several vacuolar hydrolases in Saccharomyces cerevisiae.
The pep4-3 mutation results in a 90-95% reduction in the levels of five vacuolar hydrolases in yeast, including proteinases A and B, carboxypeptidase Y, RNase(s) and the repressible alkaline phosphatase. The mutation is without effect on two secreted glycoproteins, on an enzyme of the vacuolar membrane, and on a proteinase located outside of the vacuole. Mutations at the PEP4 locus exhibit a dosage effect on the levels of some, but not all, of the enzymes whose expression requires the function of the gene.
Alkaline Phosphatase↗
Genetic properties of mutations at the PEP4 locus in Saccharomyces cerevisiae.
Yeast cells that inherit mutations at the PEP4 locus exhibit a pronounced phenotypic lag in the expression of the mutant phenotype imparted by these mutations. This lag appears to extend to all of the enzymes that are affected by the pep4-3 mutation. For at least two of the enzymatic activities, phenotypic lag shows mitotic cosegregation. Phenotypic lag is found for meiotic progeny and for mitotic segregants from heterokaryons. The phenotypic lag in the expression of the carboxypeptidase Y deficiency is abolished by nonsense mutations in either PRC1, the structural gene for carboxypeptidase Y, or PRB1, the structural gene for proteinase B. Models to explain these observations are proposed.
Cytoplasmic Granules↗
Mutant defective in processing of an enzyme located in the lysosome-like vacuole of Saccharomyces cerevisiae.
Carboxypeptidase Y, a vacuolar enzyme in Saccharomyces cerevisiae, is synthesized as a larger precursor whose apparent molecular mass is approximately 67,000 daltons. We have characterized a recessive mutation, pep4-3, that prevents maturation of this precursor. The accumulated precursor does not possess enzymatic activity. We have shown that the precursor accumulating in the pep4-3 mutant is not produced in a doubly mutant strain that also bears a mutation in the carboxypeptidase Y structural gene that eliminates production of carboxypeptidase Y. We have also shown that a nonsense fragment of carboxypeptidase Y is processed. Although there is evidence that proteinase B can catalyze the conversion of the precursor to a mature form in vitro, nonsense mutations in the structural gene for proteinase B, PRB1, do not affect the levels of carboxypeptidase Y activity, and strains bearing these mutations produce a carboxypeptidase Y of apparently normal size. Hence, proteinase B is not essential for the maturation of carboxypeptidase Y precursor in vivo. The pep4-3 mutation affects at least five vacuolar enzymes. This suggests that there is a processing event common to all of these enzymes.
Aspartic Acid Endopeptidases↗
Protein degradation, meiosis and sporulation in proteinase-deficient mutants of Saccharomyces cerevisiae.
During the process of sporulation, a/alpha diploids degrade about 50% of their vegetative proteins. This degradation is not sporulation specific, for asporogenous diploids of a/a mating type degrade their vegetative proteins in a fashion similar to that of their a/alpha counterparts. Diploids lacking carboxypeptidase Y activity, prc1/prc1, show about 80% of wild-type levels of protein degradation, but are unimpaired in the production of normal asci. Diploids lacking proteinase B activity, prb1/prb1, show about 50% of wild-type levels of protein degradation. The effect on degradation of the proteinase B deficiency is epistatic to the degradation deficit attributable to the carboxypeptidase Y deficiency. The prb1 homozygotes undergo meiosis and produce spores, but the asci and, possibly, the spores are abnormal. Diploids homozygous for the pleiotropic pep4-3 mutation show only 30% of the wild-type levels of degradation when exposed to a sporulation regimen, and do not undergo meiosis or sporulation. Neither proteinase B nor carboxypeptidase Y is necessary for germination of spores. Approximately half of the colonies arising from a/a or alpha/alpha diploids exposed to the sporulation regimen that express an initially heterozygous drug-resistance marker (can1) appear to arise from mating-type switches followed by meiosis and sporulation.
Carboxypeptidases↗
Proteolytic inactivation of the NADP-dependent glutamate dehydrogenase in proteinase-deficient mutants of Saccharomyces cerevisiae.
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Endopeptidases↗
Mapping of the proteinase b structural gene PRB1, in Saccharomyces cerevisiae and identification of nonsense alleles within the locus.
We report the mapping of the structural gene for proteinase B, PRB1. It is located 1.1 cM proximal to CAN1 on the left arm of chromosome V of Saccharomyces cerevisiae. We have identified 34 amber and 12 ochre mutations among the 126 prb1 mutations in our collection.
Chromosome Mapping↗
Septum formation, cell division, and sporulation in mutants of yeast deficient in proteinase B.
Mutants of Saccharomyces cerevisiae that carry lesions in the structural gene for proteinase B, prb1, have been isolated. Proteinase B was thought to be involved in activation of chitin synthase zymogen to allow septum formation during budding and to be involved in sporulation. The prb1 mutants are able to grow and divide and they form apparently normal septa that contain chitin. Most diploids homozygous for prb1 mutations are unable to complete sporulation.
Alleles↗
Catabolite inactivation of gluconeogenic enzymes in mutants of yeast deficient in proteinase B.
Strains of Saccharomyces cerevisiae bearing nonsense mutations in the structural gene for proteinase B (EC 3.4.22.9) have been examined for the ability to make the transition from growth on acetate to growth on glucose and for the ability to inactivate three glucoeogenic enzymes during the transition because proteinase B has been proposed by others to be responsible for the inactivation of the three enzymes during the growth transition. The mutant strains make the growth transition normally. Catabolite inactivation of hexosediphosphatase (D-fructose-1,6-biphosphate 1-phosphohydrolase, EC 3.1.3.11), malate dehydrogenase (L-malate:NAD+ oxidoreductase, EC 1.1.1.37), and phosphoenolpyruvate carboxykinase (ATP) [ATP:oxaloacetate carboxy-lyase (transphosphorylating), EC 4.1.1.49] occurred in prb1 mutants with kinetics similar to those seen in wild-type strains. We infer that proteinase B activity is not essential for the process of catabolite inactivation.
Fructose-Bisphosphatase↗
Ethanol's fluidizing effects on RBC membranes from children at risk for alcoholism.
The fluidizing effects of ethanol on membrane fluidity at 37 degrees C have been assessed using steady-state anisotropy measurements in both children at high risk for developing alcoholism and control children. Erythrocyte membranes were labeled with 1,6-diphenyl-1,3,5-hexatriene (DPH) and fluidity measurements recorded by steady-state fluorescence anisotropy for three ethanol concentrations--0, 0.5 M, and 1.0 M. The in vitro fluidizing effects of acute ethanol treatment by concentration were clearly shown in both groups. However, RBC membranes taken from children at high risk for developing alcoholism showed no significant differences in baseline membrane fluidity or to the fludizing effects of ethanol.
Alcoholism↗
Dyskinesia and neuroleptic exposure in elderly psychiatric inpatients.
A wide variation in prevalence rates of tardive dyskinesia and spontaneous orofacial dyskinesia has been reported in the elderly. To clarify these discrepancies, we studied 45 patients over the age of 60 years admitted to a short-term psychiatric unit. Standardized criteria for the diagnosis of dyskinesia were used. We found a rate of tardive dyskinesia of only 21% (7/33) in our patients having a history of neuroleptic exposure. We found no cases (0/12) of spontaneous orofacial dyskinesia. There was a significant association between tardive dyskinesia and psychiatric diagnosis, with the highest rate of tardive dyskinesia in those patients with schizophrenic disorders, followed by those with organic disorders and mood disorders, respectively. There was also a significant association between the presence of tardive dyskinesia and radiographic evidence of cortical atrophy, and a trend towards an association with leukoencephalopathy. Our results suggest that published rates of tardive and spontaneous dyskinesia in the elderly may overestimate the prevalence of these disorders, especially among geriatric patients with acute psychiatric presentations.
Aged↗
Markedly increased platelet membrane fluidity in Down syndrome with a (14q, 21q) translocation.
Abnormal platelet membrane fluidity was found in a 50-year-old woman with Down syndrome who had been experiencing a gradual mental decline. The patient's karyotype showed a triplication of the long arm of chromosome 21. The authors hypothesize that the PMF-locus, which carries the allele for increased membrane fluidity, is located on the long arm of chromosome 21. Similarities between Down syndrome and Alzheimer's disease and the possible relationship between membrane fluidity and cognitive function are mentioned.
Alzheimer Disease↗
Endoplasmic reticulum abnormality in Alzheimer's disease: selective alteration in platelet NADH-cytochrome c reductase activity.
Previous evidence suggests that the increase in platelet membrane fluidity associated with a subgroup of patients with Alzheimer's disease results from the accumulation of internal membrane. The specific activities of enzyme markers for selective cell membrane compartments were compared in platelets from subgroups of demented patients with normal or increased fluidity as well as from normal control subjects. A statistically significant change in enzyme activity was observed only for antimycin A-insensitive NADH-cytochrome reductase, a selective marker for smooth endoplasmic reticulum (SER) in platelets. This reduction was limited to the subgroup of demented patients who had increased platelet membrane fluidity, and therefore is not a nonspecific concomitant of neurodegeneration, medication exposure, or chronic illness in general. Since the platelet membrane alteration associated with Alzheimer's disease results from the inheritance of a single major locus, these results suggest that a defect in SER function may exist in brain cells as well as peripheral cells that express this genotype.
Aged↗
Shy-Drager syndrome presenting as a REM behavioral disorder.
Shy-Drager syndrome (SDS) is associated with a myriad of autonomic and neurologic impairments, including sleep disturbances. A review of the literature reveals that there are no reports of SDS presenting with an abnormality of sleep. The following case report describes a patient who was diagnosed with SDS approximately one decade after initially presenting with a progressive, polysomnographically confirmed disturbance of sleep--specifically, an REM behavioral disorder (RBD).
Aged↗
A prospective naturalistic study of electroconvulsive therapy in late-life depression.
We performed a prospective, naturalistic study using standardized clinical rating scales to characterize the effect of electroconvulsive therapy (ECT) on mood, cognition, and medical status in late-life depression. Over a 16-month period, 40 patients aged 60 years and over who fulfilled DSM-III criteria for a major depressive episode received a total of 42 ECT courses. Three patients (7%) developed significant medical complications: one had a syncopal episode due to arrhythmia, and two had symptomatic vertebral compression fractures. Confusion was noted during 13 courses (31%) and persisted at discharge in four (10%). More than half the patients were either psychotic or demented on admission, and all but three had been either unresponsive or intolerant to pharmacotherapy. All patients experienced a decrease in their depressive symptoms and more than two thirds were in complete or partial remission at discharge. Patients with psychotic depression experienced a greater improvement than patients with nonpsychotic depression, and patients with organic mental disorders experienced the same improvement as other patients. This study confirms that ECT is a safe and effective treatment of depression in late life.
Aged↗
Molecular neurobiology of Alzheimer's disease (syndrome?).
Alzheimer's disease (AD) is the most common cause of mental impairment in late life and is estimated to afflict nearly half of older adults who live beyond age 85. Although progressive dementia is a cardinal feature of patients with AD, age at symptomatic onset, rate of progression, and specific signs and symptoms vary widely. This clinical heterogeneity appears to arise in part from interindividual differences in the precise molecular events that contribute to the pathophysiology of AD, as well as from nonuniform or multifocal patterns of brain degeneration that occur during the early to middle stages of dementia. The goals of this review are to cover the substantial progress that has been made over the past 5 years in the major thematic areas of research in AD and to assemble these individual findings into a more integrated picture of the pathophysiology of the disorder. The results may have important implications for the treatment or prevention of AD.
Aged↗
Geriatric psychopharmacology: why does age matter?
Older adults respond less predictably than younger adults to most medications, typically requiring lower daily doses to achieve desired therapeutic effects and minimize adverse effects and toxicity. This unpredictability is particularly evident among the frail elderly, who are at the upper extreme of the life cycle and often suffer from central neurodegenerative disorders and/or a significant burden of comorbid medical problems. Yet this population has a burgeoning need for clinical services and in recent years has become an increasingly important focus of attention among practitioners. The goal of this review is to provide clinicians with a conceptual framework for understanding and responding to aging and age-related events that influence pharmacotherapeutics in older patients with behavioral disorders. Limitations and gaps in our knowledge base are also highlighted. The article includes a phenomenological overview of the aging process, a consideration of age-related factors that influence the pharmacokinetic and pharmacodynamic properties of psychotropic drugs, and suggested methods of enhancing medication compliance.
Aged↗