Deletions of the cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) genes, involved in the control of hydrogen sulfide biosynthesis, significantly affect lifespan and fitness components of Drosophila melanogaster.

The gasotransmitter hydrogen sulfide (H2S) is an important biological mediator, playing an essential role in many physiological and pathological processes. It is produced by transsulfuration - an evolutionarily highly conserved pathway for the metabolism of sulfur-containing amino acids methionine and cysteine. Cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) enzymes play a central role in cysteine metabolism and H2S production. Here we investigated the fitness components (longevity, stress resistance, viability of preimaginal stages, and reproductive function parameters) in D. melanogaster lines containing deletions of the CBS and CSE genes. Surprisingly, in most tests, CSE deletion improved, and CBS worsened the fitness. Lines with deletion of both CBS and CSE demonstrated better stress resistance and longevity than lines with single CBS deletion. At the same time, deletion of both CBS and CSE genes causes more serious disturbances of reproductive function parameters than single CBS deletion. Thus, a complex interaction of H2S-producing pathways and cellular stress response in determining the lifespan and fitness components of the whole organism was revealed.

FUS(1-359) transgenic mice as a model of ALS: pathophysiological and molecular aspects of the proteinopathy.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to the eventual death of motor neurons. Described cases of familial ALS have emphasized the significance of protein misfolding and aggregation of two functionally related proteins, FUS (fused in sarcoma) and TDP-43, implicated in RNA metabolism. Herein, we performed a comprehensive analysis of the in vivo model of FUS-mediated proteinopathy (ΔFUS(1-359) mice). First, we used the Noldus CatWalk system and confocal microscopy to determine the time of onset of the first clinical symptoms and the appearance of FUS-positive inclusions in the cytoplasm of neuronal cells. Second, we applied RNA-seq to evaluate changes in the gene expression profile encompassing the pre-symptomatic and the symptomatic stages of disease progression in motor neurons and the surrounding microglia of the spinal cord. The resulting data show that FUS-mediated proteinopathy is virtually asymptomatic in terms of both the clinical symptoms and the molecular aspects of neurodegeneration until it reaches the terminal stage of disease progression (120 days from birth). After this time, the pathological process develops very rapidly, resulting in the formation of massive FUS-positive inclusions accompanied by a transcriptional "burst" in the spinal cord cells. Specifically, it manifests in activation of a pro-inflammatory phenotype of microglial cells and malfunction of acetylcholine synapse transmission in motor neurons. Overall, we assume that the highly reproducible course of the pathological process, as well as the described accompanying features, makes ΔFUS(1-359) mice a convenient model for testing potential therapeutics against proteinopathy-induced decay of motor neurons.

Hsp70 family proteins seem to facilitate allo- and xenotransplantation in the rat brain.

Drosophila neuroectodermal embryonic cells were transplanted into the occipital brain region of adult rats. The first series of experiments used a transgenic strain expressing lacZ to detect the presence of Drosophila cells. The second series used a strain carrying a is lethal (ts403) in the X chromosome; this mutation strongly inhibits the synthesis of heat shock proteins (hsps) and their transport into the nuclei. Immunostaining reveals a strong induction of hsp70 in the xenografts in the first series of experiments, in which no glial scar was detectable. By contrast, where the ts mutation was xenotransplanted, the condition of xenografts was worse, and a glial scar was readily evident between the xenograft and host tissue.