Microbial Genetic Screens for Monitoring Protein Misfolding Associated with Neurodegeneration: Tools for Identifying Disease-Relevant Genes and for Screening Synthetic and Natural Compound Libraries for the Discovery of Potential Therapeutics.

Neurodegenerative Diseases (ND) are a major threat to the aging population and the lack of a single preventive or disease-modifying agent only serves to increase their impact. In the past few years, protein misfolding and the subsequent formation of neurotoxic oligomeric/aggregated protein species have emerged as a unifying theme underlying the pathology of these complex diseases. Recently developed microbial genetic screens and selection systems for monitoring ND-associated protein misfolding have allowed the establishment of highthroughput assays for the identification of cellular factors and processes that are important mediators of NDassociated proteotoxicities. In addition, such systems have facilitated the discovery of synthetic and natural compounds with the ability to rescue the misfolding and the associated pathogenic effects of aggregation-prone proteins associated with NDs. This review outlines such available systems in bacteria and yeast, whose usage will likely accelerate the pre-clinical discovery process for effective drugs against a variety of NDs with high socioeconomic impact.

[Pleiotropic effect of the mutation of streptomycin resistance in Micromonospora purpurea var. violacea]. / Pleiotropnyi éffekt mutatsii streptomitsino-rezistentnosti u Micromonospora purpurea var. violacea

Variation of different features of populations of streptomycin-sensitive and streptomycin-resistant forms of M. purpurea var. violacea, an organism producing gentamicin was studied. The population of the initial streptomycin-sensitive culture was characterized by high homogeneity with respect to the cultural, morphological and some physiological properties. The variation of the features, such as the colony size, pigment formation, auxotrophic mutations, antibiotic production significantly increased in populations grown on media with streptomycin. Mutants differing from the initial strain by a complex of cultural, morphological and physiological features and in particular the antibiotic production were isolated from populations of the streptomycin-resistant variants.

[Actinomyces streptomycini mutant blocked in streptidine biosynthesis]. / Mutant Actinomyces streptomycini, blokirovannyi po biosintezu streptidina

Mutant 170 not capable of forming streptidine and streptomycin was obtained using chemical mutagenes. This mutant can produce streptomycin only with suplementation of exogenous streptidine. Experiment with labeled C14-streptidine showed its specific incorporation in streptidine moiety of streptomycin molecule.

Inhibtory effect of colicin E2 on transport systems of Escherichia coli in the presence of the rex gene of lambda prophage.

Purified colicin E(2) was found to cause marked inhibition of the permeation rate of o-nitrophenyl-galactoside (ONPG) in several lambda-lysogenic strains of Escherichia coli in the presence of chloramphenicol to prevent prophage induction. The inhibitory effect of colicin E(2) on transport systems was analyzed with cells of E. coli CP78(lambda). The dose of colicin E(2) for the half-maximum inhibition of the ONPG-permeation rate was about 9 molecules of the colicin per bacterium under the aerobic condition, which corresponded to about 1 killing unit per bacterium. Kinetics of the transport of [(14)C]methylthiogalactoside suggested that colicin E(2) began to inhibit the influx rate of beta-galactosides within a few minutes after the colicin addition, and the maximum inhibition reached more than 80%. Extensive leakage of intracellular potassium ion and inhibition of l-proline transport also occurred at the same time. Acid solubilization of cellular deoxyribonucleic acid by the colicin was apparently delayed to the initiation of the transport inhibition. The extents of the inhibition of beta-galactoside transport and leakage of potassium ion by the colicin were extensive in cells lysogenic for wild lambda phage or lambdaind(-), whereas the extents were slight in the nonlysogenic cells or cells carrying lambdarex(-) prophage. It was concluded that the sensitization of membrane transport systems of E. coli cells to colicin E(2) was achieved by the presence of the rex gene product of lambda phage.

The mutagenicity of saccharin.

Seventeen different reports are available dealing with the mutagenic effects of saccharin. Many of these are short abstracts, carrying incomplete information. Mainly tested as its sodium salt, saccharin has been found to be weakly mutagenic in Salmonella at very high doses, in Drosophila at moderate doses, and in mice at moderate to high doses. The compound is a weak chromosome breaker in onion root tips and in Chinese hamster cells. For most of these, and for other test systems as well, a number of doubtful or negative results have also been reported. Altogether the evidence for chromosome-breaking properties is stronger than for the induction of point mutations. The overall picture is too conflicting and equivocal to classify saccharin as a proven mutagen. It is suggested that the observed contradictions might be related to the occurrence of varying amounts of impurities.