[No Effect of the p.Arg230His Variant Of The VCL Protein on the Course of the Hypertrophic Cardiomyopathy In Russian Family Carrying The p.Gln1233Ter Pathogenic Variant In The MYBPC3 Gene].

Aim      To determine specific clinical characteristics caused by a combination of the rs397516037 pathogenic variant in the myosin-binding protein C (MTBPC3) and the rs749628307 polymorphic variant in the vinculin (VCL) gene in a Russian family of carriers and to evaluate the contribution of the rs749628307 polymorphic variant in the VCL gene to the development of hypertrophic cardiomyopathy (HCMP).Material and methods  The family under study included one healthy person and 3 patients with HCMP. A targeted analysis of proband's exome was performed. A structural alignment for both forms of the VCL protein, the canonical form and the form with p.Arg230His substitution, was performed.Results The pathogenic rs397516037 variant and the potentially pathogenic rs749628307 variant were detected in the proband and several family members. A possibly damaging variant rs749628307 was detected in the proband and several family members evaluated in this study. The structural alignment confirmed that the rs749628307 variant did not alter the protein structure significantly and could not cause an impairment or loss of the protein function.Conclusion      This study demonstrated that apparently the rs749628307 variant in the VCL gene does not affect the protein structure in a pathogenetically significant way, neither does it affect the severity and form of the clinical manifestations of HCMP; therefore, it cannot be considered as pathogenic.

Expression analysis of genes involved in mitochondrial biogenesis in mice with MPTP-induced model of Parkinson's disease.

The mitochondrion is an extremely important organelle that performs various functions in the cell: e.g. energy production, regulation of respiration processes and maintenance of calcium homeostasis. Disruption of the biogenesis and functioning of this organelle can lead to cell damage and cell death. Mitochondrial dysfunction has been shown to possibly be involved in the pathogenesis of Parkinson's disease. However, the role of genes associated with mitochondrial biogenesis in the early stages of disease remains poorly understood. The objective of the present study was to analyze changes in the expression of activator (Nrf1, Ppargc1a, Prkn, and Kif1b) and repressor (Zfp746 and Mybbp1a) genes of mitochondrial biogenesis in the early stages of the development of neurodegeneration in an MPTP-induced model of presymptomatic and early symptomatic stages of PD. Statistically significant changes in expression at the mRNA level were detected for all studied genes. There was mainly a decrease in the expression of activator genes (Nrf1, Ppargc1a, Prkn, and Kif1b) at all stages of neurodegeneration, which seemed to be associated with impaired mitochondrial biogenesis and the development of neurodegeneration processes. A predominant decrease in the expression was detected for the Zfp746 and Mybbp1a repressor genes of mitochondrial biogenesis. However, in this case, it was associated with the emergence of compensatory mechanisms during the development of Parkinson's disease. The largest number of statistically significant changes was detected for the Nrf1 activator gene and the Mybbp1a repressor gene. Apparently, these two genes play the most important role in this disease.

[Possible Involvement of Genes Related to Lysosomal Storage Disorders in the Pathogenesis of Parkinson's Disease].

Parkinson's disease (PD) characterized with slow continuous degeneration of dopaminergic neurons in the substantia nigra is one of the most common neurodegenerative diseases, but its etiology and pathogenesis are not fully understood. The pathogenesis of PD involves the impairment of lysosomal autophagy, which also contributes to lysosomal storage disorders (LSDs). In this work, the expression of genes related to lysosomal autophagy: Hspa8, Lamp2, Tfam, Slc18a2, and Vps35, was analyzed in the brain tissues of mice with the earliest stage of MPTP-induced PD. The detected decrease in Hspa8 and Lamp2 mRNA levels suggests that dysfunction of lysosomal autophagy maybe involved in the earliest stages of PD pathogenesis. A decrease in the rate of lysosomal autophagy may affect the accumulation of damaged proteins and the formation of protein inclusions in PD. Genes related to the lysosome function may be involved in development of both LSD and PD at the earliest stages of these pathophysiological processes.

Whole-Transcriptome Analysis of Mouse Models with MPTP-Induced Early Stages of Parkinson's Disease Reveals Stage-Specific Response of Transcriptome and a Possible Role of Myelin-Linked Genes in Neurodegeneration.

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons. A whole-transcriptome analysis of the substantia nigra and striatum of an MPTP-induced mouse models of the earliest stages of PD was performed. Functional clustering of differentially represented transcripts revealed processes associated with the functioning of synapses, dendrites, axons, and myelination of neuronal projections. All of these processes occur in both the substantia nigra and striatum, but they are aimed at the functioning of neuron terminals in the striatum. One cluster was identified at the earliest stage modeled, i.e., "neuron projection" in the substantia nigra and "transport" in the striatum, and their number increased at subsequent stages. The number of clusters in the striatum predominates over those in the substantia nigra and there is a pronounced increase in the number of clusters from the modeled early stages to the late stages. These findings indicate that the substantia nigra and striatum have unique patterns of changes at each stage. Considering the clustering of individual processes, it was seen that there is a set of hierarchical clusters that overlap only partially at different stages and in different tissues. The data indicate a consistent involvement of the transcriptome in the pathogenesis of PD and highlight the independent role of various brain structures and individual parts of nerve cells in the formation of a response to the development of neurodegeneration. Decreased myelination of neuronal projections may be associated with the development of PD in the models considered.

[Possible involvement of neuronal nicotinic acetylcholine receptors in compensatory brain mechanisms at early stages of Parkinson's disease]. / Vozmozhnoe uchastie neironal'nykh nikotinovykh atsetilkholinovykh retseptorov v kompensatornykh mekhanizmakh mozga na rannikh stadiiakh bolezni Parkinsona.

A role of nicotinic acetylcholine receptors (nAChR) in the development of Parkinson's disease (PD) has been investigated using two mouse models corresponding to the presymptomatic stage and the early symptomatic stage of PD. Quantitative determination of nAChR in the striatum and substantia nigra (SN) was performed using the radioactive derivatives of epibatidine, -conotoxin MII, and -bungarotoxin as ligands. The number of ligand-binding sites changed differently depending on their location in the brain, the stage of the disease and the receptor subtype. Epibatidine binding decreased in the striatum to 66% and 70% at the presymptomatic and early symptomatic stages, respectively, whereas in SN a 160% increase was registered at the presymptomatic stage. The -conotoxin MII binding on striatal dopaminergic axonal terminals at the presymptomatic stage decreased by 20% and at the symptomatic stage it demonstrated a further decrease. The increase in -bungarotoxin binding at the presymptomatic stage and a decrease at the early symptomatic stage was observed in the striatum. In SN, the level of -bungarotoxin binding decreased at the presymptomatic stage and kept constant at the symptomatic stage. The significant decrease in the expression of Chrna4 and Chrna6 genes encoding 4 and 6 nAChR subunits was observed in SN at the early symptomatic stage, while a 13-fold increase in expression of the Chrna7 gene encoding the 7 nAChR subunit was detected at the presymptomatic stage. The data obtained suggest possible involvement of nAChR in compensatory mechanisms at early PD stages.

Peptides semax and selank affect the behavior of rats with 6-OHDA induced PD-like parkinsonism.

Parkinson's disease (PD) is the second most common severe neurodegenerative disorder that is characterized by progressive degeneration of dopaminergic neurons (DA neurons) in the substantia nigra pars compacta (SNpc) region of the brain. In the present study, we investigated the effects of the synthetic regulatory peptides Semax (analog of an ACTH 4-10 fragment (ACTH4-10)) and Selank (analog of immunomodulatory taftsin) on behavior of rats with 6-hydroxidopamine (6-OHDA) induced PD-like parkinsonism. It was showed that both peptides did not affect motor activity of rats in elevated cross shaped maze and passive defensive behavior of the animals. At the same time, Selank decreased level of anxiety of rats with toxic damage of DA neurons in elevated cross shaped maze. Previously such effects of Selank were revealed in healthy rodents (rats and mice) with different models of psycho-emotional stress. Therefore, toxic damage of substantia nigra does not affect the response of the rat organism on this peptide.

Genetic Analysis of BDNF, GNB3, MTHFR, ACE and APOE Variants in Major and Recurrent Depressive Disorders in Russia.

This study was conducted to explore the possibility of association between the single-nucleotide polymorphisms rs6264 of BDNF, rs5443 of GNB3, and rs1801133 of MTHFR; the In/Del polymorphism of ACE; and the ε2 allele of APOE and major depressive disorder (MDD) and recurrent depressive disorder (RDD) in an East Slavic population. Generalized multifactor dimensionality reduction (GMDR) method was applied to detect gene-gene interactions. One hundred fifty patients with RDD (101 females and 49 males) and 208 patients with MDD (115 females and 93 males) were included in the study. The comparison group consisted of 200 unrelated individuals. There was no significant difference in genotype distributions or allele frequencies between the controls and any of the diagnostic groups. Nevertheless, the frequency of the G allele of rs1801133 of MTHFR was higher in the RDD group and the frequency of the C allele of rs6264 of BDNF was higher in the MDD group. The difference between the controls and specific disease groups almost reached statistical significance (P = 0.08). A GMDR did not reveal optimal two- and three-dimensional models with significant prediction accuracies (P ˃ 0.05) for the MDD or RDD groups.

ITPR1 gene p.Val1553Met mutation in Russian family with mild Spinocerebellar ataxia.

BACKGROUND: Spinocerebellar ataxias (SСAs) are a highly heterogeneous group of inherited neurological disorders. The symptoms of ataxia vary in individual patients and even within the same SCA subtype. A study of a four-generation family with autosomal dominant (AD) non-progressive SCA with mild symptoms was conducted. The genotyping of this family revealed no frequent pathogenic mutations. So the objective of this study was to identify the genetic causes of the disease in this family with the technology of whole-exome sequencing (WES). METHODS AND RESULTS: WES, candidate variant analysis with further Sanger sequencing, mRNA secondary structure prediction, and RSCU analysis were performed; a heterozygous missense mutation in ITPR1 was identified. CONCLUSION: Our study confirms the fact that ITPR1 gene plays a certain role in the pathogenesis of SCAs, and, therefore, we suggest that c.4657G>A p.Val1553Met) is a disease-causing mutation in the family studied.

Expression analysis of genes of ubiquitin-proteasome protein degradation system in MPTP-induced mice models of early stages of Parkinson's disease.

Parkinson's disease (PD) is the second most common severe neurodegenerative disorder that is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. However, causes and mechanisms of the development of this disorder are still not fully understood. At the same time, it is well known that dysfunction of the ubiquitin-proteasome protein degradation system (UPPDS) is one of the major mechanisms of the pathogenesis of PD. In this study we have investigated alterations in expression of Uchl3, Ubr7, Ube3c, Usp19, Usp39, Ube2k, Ube2d3, Ube2m, Ube2g1 genes, which are directly involved in the functioning of the UPPDS, using the real-time PCR in mice with the MPTP-induced pre-symptomatic and early symptomatic stages of PD. We have revealed reduction of expression of all genes studied in the striatum of brain in mice with the MPTP-induced pre-symptomatic and early symptomatic stages of PD and the majority of genes in the substantia nigra: Uchl3, Ubr7, Ube3c, Usp39, Ube2k, Ube2d3, Ube2g1 at pre-symptomatic stage and Uchl3, Ube3c, Usp39, Ube2k, Ube2m at early symptomatic stage of PD. Decreasing transcript levels of the genes studied may indicate decrease in the efficiency of the UPPDS on the whole which in turn may lead to the accumulation of abnormal proteins and toxic protein aggregates and subsequent death of the neurons. Thus, our findings appear to indicate that a violation of this system can play an important role in the development of pathogenic processes that occur at the earliest stages of the disease.

[Analysis of mutations in patients with suspected autosomal dominant form of the Parkinson disease].

The Parkinson disease (PD) is a severe neurological disorder. Diverse genetic systems and environmental factors are involved in the pathogenesis of this disease. However, despite extensive research into the disease, its causes are not fully elucidated, and the exact spectrum of genes and mutations involved in the development of hereditary forms of PD has not been fully clarified yet. The present work is devoted to the analysis of mutations that lead to the development of monogenic forms of PD in patients with suspected autosomal dominant form of PD using Multiplex Ligation-dependent Probe Amplification (MLPA). We have identified several mutations (G2019S in LRRK2, heterozygous deletions of 2-3, 3-4 exons and heterozygous duplication of 2-4 exons in PARK2, deletion of 3 exon in PARK7) that lead to the development of PD in only 7 people out of 70 (18.4%), which suggests the need for further search of new mutations, for example, using exome sequencing. In the future it will help to develop the molecular genetic tests for early preclinical diagnosis and risk evaluation of the development of PD, and to understand better the causes and mechanisms of this disease.

[Transcriptome alteration in hippocampus under the treatment of tuftsin analog Selank].

The effect of single and course administration of Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) in the dose 200 microg/kg on the rat hippocampus transcriptional profile were studied using cDNA microarray technology. It was shown that mRNA levels of 36 genes changed more than 2-fold after a single intranasal Selank administration, and 20 genes--after course administration. It should be noted that most of them encode proteins associated with the plasma membrane (including transmembrane proteins). This suggests that Selank is able to regulate ion homeostasis of hippocampal cells and thereby modulate different ion-dependent processes, which include the processes of learning and memory formation.

MicroRNAs: possible role in pathogenesis of Parkinson's disease.

Parkinson's disease is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons from the substantia nigra pars compacta of human brain. However, causes and mechanisms of the progression of the disease are not yet fully clarified. To date, investigation of the role of miRNAs in norm and pathology is one of the most intriguing and actively developing areas in molecular biology. MiRNAs regulate expression of a variety of genes and can be implicated in pathogenesis of various diseases. Possible role of miRNAs in pathogenesis of Parkinson's disease is discussed in this review.

[Analysis of the rs12720208 single-nucleotide polymorphism of the FGF20 gene in Russian patients with sporadic Parkinson's disease].

Parkinson's disease (PD) is a multifactorial neurodegenerative disease whose pathogenesis involves a number of genes and environmental factors. The FGF20 gene encoding the fibroblast growth factor and paying an important role neuron proliferation and survival is one of candidate genes of PD. There is evidence that this gene is also involved in the control of alpha-synuclein (SNCA) gene expression. The rs12720208 single-nucleotide polymorphism (SNP) in the FGF20 gene has been found to be associated with PD; it has been located to the 3'-UTR binding site for microRNA-433, which is involved in the control of FGF20 expression. Therefore, the frequency distribution of rs12720208 genotypes in the FGF20 gene has been analyzed in a sample of patients with sporadic PD and a control sample of the Russian population. The results have not shown any effect of rs12720208 in the FGF20 gene on the risk of PD in patients residing in Russia (OR = 0.95, the 95% confidence interval (CI) is 0.55-1.63, p = 0.9).

[Changes in expression of the genes for chemokines, cytokines, and their receptors in response to selank and its fragments].

A study of the immunomodulating effect of selank showed that the total peptide and its fragment significantly change the expression of the genes for chemokines, cytokines, and their receptors in mouse spleen 6 and 24 h after administration of a single dose. Changes in the mRNA level of the majority of the genes under study were similarly observed after the administration of Gly-Pro, which was earlier identified as a selank pharmacophor, a minimum fragment with anitiviral activity. Pharmacological preparations based on endogenous regulatory peptides are studied intensely because they are the most promising class of drugs and have almost no side effects. The class includes selank, which is a synthetic analog of taftsin. Selank exerts anxiolytic and nootropic effects and, on the other hand, has pronounced antiviral properties.

[Analysis of single nucleotide polymorphism rs415430 in the WNT3 gene in the Russian population with the Parkinson disease].

The Parkinson disease (PD) is the second most common progressive neurodegenerative disorder that arises due to degeneration of dopaminergic neurons. The causes of this disease are still unknown, but a number of genes involved in pathogenesis of familial and sporadic forms of PD has been identified. According to recent data of genome wide association studies (GWAS), single nucleotide polymorphisms (SNPs) in these genes (including MAPT locus) may play an important role in the development of PD. Therefore, we analyzed distribution of genotype frequencies of SNP rs415430 in the WNT3 gene in the Russian patients with sporadic PD and in the Russian population controls (OR = 0.84, Confidence Interval (95% CI) 0.58-1.23, p = 0.39). It was concluded that SNP rs415430 in the WNT3 gene was not associated with the risk of development of PD.

[Expression of GSK3B gene in peripheral blood in patient with Parkinson's disease].

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Detecting changes in gene expression in untreated de novo patients with PD is important for understanding disease pathogenesis and for identifying biomarkers for preclinical stage of PD. In this study we investigate expression of gene of Glycogen synthase kinase-3 beta (GSK3B) in the peripheral blood of different groups of patients with neurological diseases using reverse transcription reaction and real-time polymerase chain reaction (PCR). Our results suggest that the expression levels of GSK3B can't serve as a biomarker for early stages of PD.

[Transcranial sonography in Parkinson's disease].

An abnormal hyperechogenecity of substantia nigra is thought to be the most characteristic sonographic feature in Parkinson's disease (PD). However specificity and sensitivity of the ultrasound method should be refined. Using transcranial sonography, authors have examined 168 patients with different clinical signs of parkinsonism, including 99 patients with idiopathic PD, and 56 patients without extrapyramidal disorders. Hyperechogenecity of substantia nigra was found in 93% of patients and in 14% of controls. It has been shown that this biomarker can successfully discriminate PD from a number of similar disorders (essential tremor, atypical parkinsonian syndromes). Sonographic features of late, early and genetically determined parkinsonism specifying some pathogenetic aspects of these pathologies are described. Taking into account the data obtained, transcranial sonography can be considered as a highly informative method in the differential and early diagnosis of PD.

Molecular mechanisms of pathogenesis of Parkinson's disease.

Parkinson's disease is a complex disease characterized by a progressive degeneration of nigrostriatal dopaminergic neurons. The development of this condition is defined by the interaction between the genetic constitution of an organism and environmental factors. Analysis of the genes associated with development of monogenic forms of disease has allowed pointing out several mechanisms involved in Parkinson's disease pathogenesis such as the ubiquitin-proteasome degradation, differentiation of dopaminergic neurons, mitochondrial dysfunction, oxidative damage, and others. In this review, a variety of data which throw light on molecular mechanisms underlying pathogenesis of Parkinson's disease will be considered.

[Analysis of the alpha-synuclein gene dosage variation associated with autosomal dominant form of ParkinsonTs disease].

Fifty-two patients that had ParkinsonTs disease with autosomal dominant type of inheritance were analyzed for the presence of duplications and triplications in exons 4--6 of alpha-synuclein gene using real-time PCR with Taq-Man probes. No mutations involving the examined exons dosage were revealed in alpha-synuclein gene. Thus, mutations modifying copy number of alpha-synuclein gene do not significantly affect the pathogenesis of the autosomal dominant form of ParkinsonTs disease in patients from Russia.