Skvortsova Vi

Analysis of heavy neurofilament subunit gene polymorphism in Russian patients with sporadic motor neuron disease (MND)

Motor neuron disease (MND) results in the selective degeneration of motor neurons in the cerebral cortex, brain stem and spinal cord. The most common form of MND is amyotrophic lateral sclerosis (ALS). MND is complex and many genetic systems may be involved in the pathogenesis of this disease. Pathological and animal studies implicate neurofilament involvement in MND. The heavy subunit (NEFH) tail domain contains a repeated motif. In humans, there are two common variants: the 45 motif repeats long allele (L) and 44 motif repeats short allele (S). Previous studies have shown that the NEFH tail may be involved in the pathogenesis of MND. To investigate whether the L/S genotypes of the NEFH gene are associated with MND, we studied the frequency of L and S alleles in sporadic MND patients and a control population from Moscow. We observed a difference in SS genotype frequency between the control population and sporadic MND patients from Moscow. It was established that the SS genotype is sufficiently higher in sporadic MND patients. Moreover, we determined that patients with the SS genotype have the highest value of loss of the total clinical score. In summary, we conclude that the NEFH gene is involved in the pathogenesis of sporadic MND. The SS genotype represents a risk factor for the development and progression of sporadic MND in the Moscow population.

The Effect of Semax and Its C-End Peptide PGP on the Morphology and Proliferative Activity of Rat Brain Cells During Experimental Ischemia: A Pilot Study

The neuropeptide preparation Semax (Met-Glu-His-Phe-Pro-Gly-Pro) has been employed successfully in clinical practice for treating patients with severe brain blood circulation disorders. In spite of numerous studies, many aspects of the therapeutic effects of this preparation remain unknown. In this context, the effects of Semax and its C-end tripeptide PGP on the functional morphology of nervous tissue cells were studied in the normal rat brain and in a model of incomplete global rat brain ischemia. In control animals, both peptides activated the capillary network and caused similar morphological changes to neurons and the neuropil regions. We show here for the first time at the histological level that Semax and PGP increased proliferation of the neuroglia, blood vessel endothelium, and progenitor cells in the subventricular zone. In these experimental conditions, only Semax abated the manifestation of ischemic damage to the nervous tissue. This was probably attributable to a decrease in vascular stasis symptoms as well as the trophic effect of the peptide.

Expression of sphingomyelin synthase 1 gene in rat brain focal ischemia

Metabolites of the sphingomyelin cycle are reported to play an important role in neuronal death after ischemia. To elucidate the involvement of the key enzyme of this cycle, sphingomyelin synthase (SMS), in the mechanism underlying cerebral ischemia, we, for the first time, investigated changes in the mRNA expression of the SMS1 gene in rats after focal cerebral ischemia. According to our histological analysis, the damaged area is localized only in the ipsilateral cortex. In the ischemic cortex, the level of SMS1 transcripts was decreased at 3 and 24 h after occlusion, and at 72 h it had returned to the control level. A reduced level of SMS1 mRNA expression in the subcortex of rats with occlusion and sham-operated animals also was appeared during the first 24 h after surgery. This could be attributed to the effect of surgical stress. Seventy-two hours after occlusion, SMS1 mRNA expression in subcortex of ischemic rats was still at a decreased level; this may be considered to be a somewhat distant extended effect. Our results show the early response of the SMS1 gene that can be induced by both ischemia and stress. The results also suggest that inhibition of SMS1 mRNA expression may contribute to ceramide accumulation in a damaged cortex.

C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population

Cohorts of amyotrophic lateral sclerosis (ALS) patients and control individuals of Caucasian origin from the Central European Russia (Moscow city and region) were analyzed for the presence of hexanucleotide repeat GGGGCC expansion within the first intron of the C9ORF72 gene. The presence of a large (>40) repeat expansion was found in 15% of familial ALS cases (3 of 20 unrelated familial cases) and 2.5% of sporadic ALS cases (6 of 238) but in none of control cases. These results suggest that the frequency of C9ORF72 hexanucleotide repeats expansions in the Central European Russian ALS patients is significantly lower than in Western European or Northern American ALS patients of Caucasian origin but higher than in Asian ALS patients.

FUS gene mutations associated with familiar forms of amyotrophic lateral sclerosis affect cellular localization and aggregation properties of the encoded protein

123 1 It is widely accepted that alterations in the metab olism and function of aggregation prone proteins play a crucial role in the pathogenesis of many neurode generative disorders belonging to the group of protein opathies. Conformational changes of these proteins resulting in aberrant structure followed by their aggre gation and formation of pathological inclusions in the nervous system are considered to be key pathogenic events of proteinopathies, causing progressive neuro degeneration [1, 2]. Control and restitution of the metabolism of such proteins is one of the major ways for developing new therapeutic approaches for various neurodegenerative diseases [1, 3, 4]. Modeling of pro teinopathies using cell culture allows reproducing main elements of molecular pathology, correlating with metabolic dysfunction of aggregation prone pro teins. This approach also makes it possible to study the nature and mechanisms of neurodegenerative changes as well as to perform primary screening of potential therapeutics, which are able to directly interfere with these mechanisms [5].

Effects of ischemia on the expression of neurotrophins and their receptors in rat brain structures outside the lesion site, including on the opposite hemisphere

Neurotrophins stimulate the regeneration of neural tissue after lesions. It is also known that the sources of neurogenesis and cerebral function recovery are predominantly located in subcortical brain structures. The effects of ischemia on the expression of genes that encode neurotrophins (Bdnf, Ngf, Nt-3) and their receptors (TrkB, TrkA, TrkC, p75) in brain structures outside the lesion site were studied 3, 24, and 72 h after irreversible unilateral occlusion of the middle cerebral artery in rats. Changes in the mRNA expression of these genes were assessed by relative quantification using real-time RT-PCR. Sham surgery was found to stimulate the expression of genes that encode neurotrophins (Bdnf, Ngf) and their receptor (p75). It has been shown that ischemia influenced the expression of neurotrophins (Bdnf, Ngf, Nt-3) and their receptors (TrkB, TrkA, TrkC, p75) in brain structures outside the lesion focus, including the contralateral hemisphere. The downregulation of Bdnf and TrkB transcripts and Ngf and TrkA upregulation in the contralateral cortex on the first day of ischemia obviously reflected stress response. On day 3, Nt-3 transcription increased in all investigated structures outside the lesion focus. In the contralateral hemisphere, relative levels of TrkA and TrkC mRNA expression increased, while p75 expression decreased. Presumably, the observed changes in gene transcription serve to facilitate neuroplasticity and neural tissue regeneration.

Tripeptide Pro-Gly-Pro affects rat-brain transcriptome during focal ischemia

Tripeptide Pro-Gly-Pro (PGP) belongs to the group of biologically active regulatory peptides that are resistant to peptidases. This makes it possible to use it as a C-terminal fragment of peptide agents Semax and Selank. In recent years, the independent effects of PGP were revealed. The question was raised of whether PGP contributes to the action of pharmaceutical agents that contain this peptide as a fragment. Genome-wide analysis was performed to examine the PGP impacts on the transcriptome of rat cerebral cortex in experimental ischemia. We compared the gene expression levels in animals exposed to ischemia and PGP and in rats of the ischemia control group in 3 and 24 h after the permanent occlusion of the left middle cerebral artery. The altered expression of 29 genes was detected in 3 h, while the altered expression of 57 genes was detected in 24 h. The proteins encoded by these genes fulfill various functions, such as cytokines, transport proteins, transcription factors, transmembrane receptors, etc. Biological processes associated with the genes with altered expression under experimental conditions were determined. It was shown that PGP affects a number of processes involved in the functioning of various body systems. The expression of genes associated with the immune response process changed most significantly a day after the occlusion of the middle cerebral artery. The predominant effect of the suppression of the expression of the immune system genes was observed.

Detection of autoantibodies to potentially amyloidogenic protein, gamma-synuclein, in the serum of patients with amyotrophic lateral sclerosis and cerebral circulatory disorders

In this study, we analyzed serum for the presence of antibodies to gamma-synuclein in patients with amyotrophic lateral sclerosis (ALS) compared to the control group of patients with other neurological diseases and healthy control donors. As a result, antibodies against gamma-synuclein are not an ALS-specific feature and have been identified in patients with ALS as well as in the control group patients. Patients with the impaired cerebral circulation showed increased incidence of autoantibodies to gamma-synuclein, yet the difference lacks statistical representativeness due to limited sample size.

The FUS protein: Physiological functions and a role in amyotrophic lateral sclerosis

Certain forms of amyotrophic lateral sclerosis (ALS) are associated with an altered compartmentalization of FUS and its aggregation in the cytoplasm of motoneurons. FUS is a DNA/RNA-binding protein that is involved in DNA repair and the regulation of transcription, splicing, RNA transport, and local translation. Two theories have been proposed to explain the mechanism of the pathophysiological process in ALS. The theories attribute degeneration of motor neurons to either loss or gain of FUS function. The review describes the main physiological functions of FUS and considers evidence for each of the theories of ALS pathogenesis.

Recent advances in rehabilitation of stroke survivors.

This report discusses the newest approaches to rehabilitation of post-stroke patients. Recent studies have clinical implications for the treatment of stroke at all stages, and chronic aphasia.