[A mice model of amyotrophic lateral sclerosis expressing mutant human FUS protein].

UNLABELLED: BACKGROUND AND ОBJECTIVE: Loss of conformation and function of sufficient number of proteins with high aggregation capacity plays an important role in the pathogenesis of many neurodegenerative disorders (NDD). Due to a recent discovery of new array of proteins with the capacity to form aggregates of nonamyloid type, new NDD models as well as a new level of understanding in vivo models which are already exist is needed. DNA/RN A binding proteins - FUS and TDP-43 play a crucial role in the pathogenesis of some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The objective of the study was to develop a new ALS transgenic model. MATERIAL AND METHODS: In cell culture experiments, we studied mutant FUS proteins capable to form intracellular deposits morphologically similar to those observed in the autopsy material of ALS patients. RESULTS AND CONCLUSION: We created a transgenic mice line, in which a pathogenic form of human FUS protein was expressed in the nervous system. That led to the aggregation of FUS protein in spinal cord and motor neurons with the following degeneration and development of a phenotype, similar to the human ALS disease phenotype, in young grown-up animals. This neurodegenerative phenotype corresponds to a great number of clinical manifestations of human ALS and is an adequate transgenic model of the disease.

[Study into molecular targets of a neuroprotective compound dimebon using a transgenic mice line].

In the present study we have used a transgenic mice overexpressing an amyloidogenic protein, gamma-synuclein, in the nervous system to address the effect of dimebon on proteinopathy progression. Neuroprotective effect of chronic dimebon administration in these mice at organismal level was confirmed by the increased lifespan. Using histological and biochemical approaches we have demonstrated that dimebon reduced the number of amyloid inclusions in spinal cord of transgenic animals and decreased the content of ubiquitinated proteins in detergent-insoluble fractions. These effects are likely to occur at the level of aggregated protein species, since transgene expression was not altered. Thus, pathological protein aggregation serves as one of dimebon targets in neurodegeneration.

[Proteinopathies--forms of neurodegenerative disorders with protein aggregation-based pathology].

A number of neurodegenerative disorders have recently been coalesced into a group of proteinopathies because of the similarity of molecular mechanisms underlying their pathogenesis. A key step in the development of proteinopathies is a structural change that triggers aggregation of proteins, which are intrinsically prone to form aggregates due to their physical and chemical properties. Present review is devoted to the recent progress in the field of proteinopathies with specific focus on properties of aggregate-prone proteins, main stages of the development of molecular pathology and the role of cellular clearance systems in progression of neurodegeneration. Recent modifications in the nomenclature of neurodegenerative diseases will also be addressed.

Dimebon reduces the levels of aggregated amyloidogenic protein forms in detergent-insoluble fractions in vivo.

Aggregation of proteins liable to assembling into fibrils with subsequent formation of amyloid incorporations is an important component in the pathogenesis of many neurodegenerative diseases. Dimebon, a Russian drug, reduces the content of detergent-insoluble fibrillar forms of synuclein, the main protein component of pathological incorporations in neurons of transgenic mouse strain used in the study.

[Analysis of the chromocenter DNA composition in polytene chromosomes of Drosophila orena ovarian nurse cells].

Chromocenter DNA fragments of polytene chromosomes of Drosophila orena ovarian nurse cells were cloned from a region-specific library (Dore 1) in a plasmid vector to yield 133 clones. A total of 76 clones were selected and sequenced. The total length of the sequenced fragments was 23940 bp. Analysis with several software packages revealed various repetitive sequences among the fragments of the Dore 1 library, including mobile genetic elements (25 fragments homologous to various LTR retrotransposons, five fragments homologous to LINEs, three fragments homologous to Helitrons, one fragment homologous to Polinton, and one fragment homologous to the mini-me non-LTR retrotransposon), four minisatellites, a satellite (SAR_DM), the (TATATG)n simple sequence repeat, and a low-complexity T-rich repeat. Sequences homologous to protein-coding genes were also found in the Dore 1 library. Various repetitive DNA sequences and gene homologs were identified as conserved sequences of pericentric heterochromatin of polytene chromosomes of ovarian nurse cells in nine species of the melanogaster species subgroup.

[Targeted inactivation of gamma-synuclein gene affects anxiety and exploratory behaviour of mice].

Gamma(gamma)-synuclein is a member of synuclein family of cytoplasmic and predominantly neuronal proteins found only in vertebrates. Gamma-synuclein is abundant in axons and presynaptic terminals of neurons localized in brain regions involved in emotions, learning and memory. However, the role of gamma-synuclein in these brain functions was not previously assessed. We have demonstrated for the first time that the loss of gamma-synuclein results in a significant increase in the level of orientation response in novel environment and decrease in the level of state anxiety.

[The effects of inbreeding and low temperature on the pattern of chromosome synapsis in the ovarian nurse nuclei of Drosophila melanogaster strains].

The effects of inbreeding and low temperature on the pattern of homologous chromosome synapsis in ovarian nurse cell nuclei of Drosophila melanogaster strains were studied. Exposure to decreased temperature (16 degrees C) caused a noticeable increase in the rate of asynapses of homologous chromosomes, whereas this effect was insignificant for F30 inbreeding generation. Long-term inbreeding has a substantial effect on the relative positions of chromosomes in the nurse cell nuclei. This is visually evident only in the interstrain hybrids between highly inbred strains LA (F923) and HA (F923) or between either strain and laboratory strain Canton S or the flies from the natural population, where abnormalities in homologous chromosome synapsis are observed in virtually all nuclei.

[Molecular-cytogenetic analysis of pericentromeric heterochromatin in ovarian nurse cells of Drosophila melanogaster subgroup species].

Evolutionary rearrangements of pericentromeric heterochromatin among Drosophila melanogaster subgroup species have been investigated. Region-specific DNA library from Drosophila orena ovarian nurse cell chromocenter has been obtained by microdissection of polytene chromosomes. The probe was localized on ovarian nurse cells chromosomes of D. melanogaster subgroup species using fluorescent in situ hybridization. Sequences homologous to the sequences of the DNA-probe were found in chromocenter and pericentromeric regions of D. orena polytene chromosomes; and in all pericentromeric regions of other species with several exceptions. So, there was no labeling on one of the arms of D. simulans chromosome 2 but such sequences were present on telomere of D. erecta chromosome 3 and in regions adjacent to the brightly DAPI-stained heterochromatic blocks of D. yakuba, D. santomea and D. teissieri chromosomes 2 and 3. At S6 stage (secondary reticulate nucleus), the labeled chromatin in D. orena could be found mostly within a restricted area and no such chromatin could be detected throughout the rest of the nucleus. On the contrary, the labeled DNA was spread diffusely in the nuclei of other species at this stage.