Effects of Age and MPTP-Induced Parkinson's Disease on the Expression of Genes Associated with the Regulation of the Sleep-Wake Cycle in Mice.

Parkinson's disease (PD) is characterized by a long prodromal period, during which patients often have sleep disturbances. The histaminergic system and circadian rhythms play an important role in the regulation of the sleep-wake cycle. Changes in the functioning of these systems may be involved in the pathogenesis of early stages of PD and may be age-dependent. Here, we have analyzed changes in the expression of genes associated with the regulation of the sleep-wake cycle (Hnmt, Hrh1, Hrh3, Per1, Per2, and Chrm3) in the substantia nigra (SN) and striatum of normal male mice of different ages, as well as in young and adult male mice with an MPTP-induced model of the early symptomatic stage (ESS) of PD. Age-dependent expression analysis in normal mouse brain tissue revealed changes in Hrh3, Per1, Per2, and Chrm3 genes in adult mice relative to young mice. When gene expression was examined in mice with the MPTP-induced model of the ESS of PD, changes in the expression of all studied genes were found only in the SN of adult mice with the ESS model of PD. These data suggest that age is a significant factor influencing changes in the expression of genes associated with sleep-wake cycle regulation in the development of PD.

Genetic Architecture of Parkinson's Disease.

Year 2022 marks 25 years since the first mutation in familial autosomal dominant Parkinson's disease was identified. Over the years, our understanding of the role of genetic factors in the pathogenesis of familial and idiopathic forms of Parkinson's disease has expanded significantly - a number of genes for the familial form of the disease have been identified, and DNA markers for an increased risk of developing its sporadic form have been found. But, despite all the success achieved, we are far from an accurate assessment of the contribution of genetic and, even more so, epigenetic factors to the disease development. The review summarizes the information accumulated to date on the genetic architecture of Parkinson's disease and formulates issues that need to be addressed, which are primarily related to the assessment of epigenetic factors in the disease pathogenesis.

Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity.

Mutations in the GBA1 gene represent the major genetic risk factor for Parkinson's disease (PD). The lysosomal enzyme beta-glucocerebrosidase (GCase) encoded by the GBA1 gene participates in both the endolysosomal pathway and the immune response. Disruption of these mechanisms is involved in PD pathogenesis. However, molecular mechanisms of PD associated with GBA1 mutations (GBA-PD) are unknown today in particular due to the partial penetrance of GBA1 variants in PD. The modifiers of GBA1 penetrance have not been elucidated. We characterized the transcriptomic profiles of cells from the substantia nigra (SN) of mice with co-injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and selective inhibitor of GCase activity (conduritol-ß-epoxide, (CBE)) to mimic PD bearing GCase dysfunction (MPTP+CBE), mice treated with MPTP, mice treated with CBE and control mice treated with injection of sodium chloride (NaCl) (vehicle). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Functional clustering of differentially represented transcripts revealed more processes associated with the functioning of neurogenesis, inflammation, apoptosis and autophagy in MPTP+CBE and MPTP mice than in vehicle mice, with a more pronounced alteration of autophagy processes in MPTP+CBE mice than in MPTP mice. The PI3K-Akt-mTOR signaling pathway may be considered a potential target for therapy in PD with GCase dysfunction.

Tissue-Specific Ferritin- and GFP-Based Genetic Vectors Visualize Neurons by MRI in the Intact and Post-Ischemic Rat Brain.

(1) Background: Neurogenesis is considered to be a potential brain repair mechanism and is enhanced in stroke. It is difficult to reconstruct the neurogenesis process only from the histological sections taken from different animals at different stages of brain damage and restoration. Study of neurogenesis would greatly benefit from development of tissue-specific visualization probes. (2) Purpose: The study aimed to explore if overexpression of ferritin, a nontoxic iron-binding protein, under a doublecortin promoter can be used for non-invasive visualization of neurogenesis using magnetic resonance imaging (MRI). (3) Methods: Ferritin heavy chain (FerrH) was expressed in the adeno-associated viral backbone (AAV) under the doublecortin promoter (pDCX), specific for young neurons, in the viral construct AAV-pDCX-FerrH. Expression of the enhanced green fluorescent protein (eGFP) was used as an expression control (AAV-pDCX-eGFP). The viral vectors or phosphate-buffered saline (PBS) were injected intracerebrally into 18 adult male Sprague-Dawley rats. Three days before injection, rats underwent transient middle-cerebral-artery occlusion or sham operation. Animals were subjected to In vivo MRI study before surgery and on days 7, 14, 21, and 28 days after injection using a Bruker BioSpec 11.7 T scanner. Brain sections obtained on day 28 after injection were immunostained for ferritin, young (DCX) and mature (NeuN) neurons, and activated microglia/macrophages (CD68). Additionally, RT-PCR was performed to confirm ferritin expression. (4) Results: T2* images in post-ischemic brains of animals injected with AAV-pDCX-FerrH showed two distinct zones of MRI signal hypointensity in the ipsilesioned hemisphere starting from 14 days after viral injection-in the ischemic lesion and near the lateral ventricle and subventricular zone (SVZ). In sham-operated animals, only one zone of hypointensity near the lateral ventricle and SVZ was revealed. Immunochemistry showed that ferritin-expressing cells in ischemic lesions were macrophages (88.1%), while ferritin-expressing cells near the lateral ventricle in animals both after ischemia and sham operation were mostly mature (55.7% and 61.8%, respectively) and young (30.6% and 7.1%, respectively) neurons. RT-PCR confirmed upregulated expression of ferritin in the caudoputamen and corpus callosum. Surprisingly, in animals injected with AAV-pDCX-eGFP we similarly observed two zones of hypointensity on T2* images. Cellular studies also showed the presence of mature (81.5%) and young neurons (6.1%) near the lateral ventricle in both postischemic and sham-operated animals, while macrophages in ischemic lesions were ferritin-positive (98.2%). (5) Conclusion: Ferritin overexpression induced by injection of AAV-pDCX-FerrH was detected by MRI using T2*-weighted images, which was confirmed by immunochemistry showing ferritin in young and mature neurons. Expression of eGFP also caused a comparable reduced MR signal intensity in T2*-weighted images. Additional studies are needed to investigate the potential and tissue-specific features of the use of eGFP and ferritin expression in MRI studies.

The spectrum of SDHD mutations in Russian patients with head and neck paraganglioma.

AIM OF THE STUDY: It was found that the mutations in the SDHD gene, encoding one of subunits of the succinate dehydrogenase complex, lead to the development of head and neck paraganglioma (HNPGL). We analyzed this gene in 91 patients with HNPGL from Russia. MATERIALS AND METHODS: DNA was isolated from the whole blood. A screening for mutations was performed by Sanger sequencing. RESULTS: We revealed three missense mutations that have been described previously: p.Pro81Leu, p.His102Arg, p.Tyr114Cys. Moreover, we identified a novel potentially pathogenic variant (p.Trp105*). CONCLUSIONS: We found that mutations in the SDHD gene were less common in Russian patients compared with the majority of European populations. It was shown that the p.His102Arg mutation is a major mutation in Russia. We confirmed the previous suggestion that a bilateral localization of the tumor and the carotid type represent a marker of the genetically determined form of HNPGL.

Second mutation in PARK2 is absent in patients with sporadic Parkinson's disease and heterozygous exonic deletions/duplications in parkin gene.

AIM OF THE STUDY: Mutations in PARK2 are one of the causes of Parkinson's disease (PD). Deletions and duplications/triplications of one exon or exon groups account for a large proportion of mutations in the gene. At the present time, it is still not fully clear whether heterozygous mutations cause the development of PD. Our study aimed at conducting screening for mutations in PARK2 in patients with a sporadic form of PD to clarify the role of PARK2 in the development of PD. MATERIALS AND METHODS: The cohort of 327 patients with PD was screened by quantitative real-time polimerase chain reaction (PCR) with subsequent Sanger sequencing. RESULTS: It was found that a sufficiently large proportion of these patients (21 patients, 6.4%) were carriers of heterozygous deletions or duplications in PARK2. Analysis of PARK2 exon rearrangement carriers for the presence of point mutations in PARK2 did not reveal any variants with pathogenic significance. CONCLUSIONS: Thus, our data indicate that heterozygous deletions and duplications can play an important role in the pathogenesis of PD and can be considered as dominant mutations with low penetrance.

Quaternary-Linked Changes in Structure and Dynamics That Modulate O2 Migration within Hemoglobin's Gas Diffusion Tunnels.

Atomistic molecular dynamics simulations of diffusion of O2 from the hemes to the external solvent in the α- and ß-subunits of the human hemoglobin (HbA) tetramer reveal transient gas tunnels that are not seen in crystal structures. We find here that the tunnel topology, which encompasses the reported experimental Xe binding cavities, is identical in HbA's T, R, and R2 quaternary states. However, the O2 population in the cavities and the preferred O2 escape portals vary significantly with quaternary structure. For example, most O2 molecules escape from the T ß-subunit via the cavity at the center of the tetramer, but direct exit from the distal heme pocket dominates in the R2 ß-subunit. To understand what triggers the quaternary-linked redistribution of O2 within its tunnels, we examined how the simulated tertiary structure and dynamics of each subunit differs among T, R, and R2 and report that minor adjustments in α-chain dynamics and ß-heme position modulate O2 distribution and escape in HbA. Coupled to the ß-heme position, residue ßF71 undergoes quaternary-linked conformations that strongly regulate O2 migration between the ß-subunit and HbA's central cavity. Remarkably, the distal histidine (HisE7) remains in a closed conformation near the α- and ß-hemes in all states, but this does not prevent an average of 23, 31, and 46% of O2 escapes from the distal heme pockets of T, R, and R2, respectively, via several distal portals, with the balance of escapes occurring via the interior tunnels. Furthermore, preventing or restricting the access of O2 to selected cavities by mutating HisE7 and other heme pocket residues to tryptophan reveals how O2 migration adjusts to the bulky indole ring and sheds light on the experimental ligand binding kinetics of these variants. Overall, our simulations underscore the high gas porosity of HbA in its T, R, and R2 quaternary states and provide new mechanistic insights into why undergoing transitions among these states likely ensures effective O2 delivery by this tetrameric protein.

O2 and Water Migration Pathways between the Solvent and Heme Pockets of Hemoglobin with Open and Closed Conformations of the Distal HisE7.

Hemoglobin transports O2 by binding the gas at its four hemes. Hydrogen bonding between the distal histidine (HisE7) and heme-bound O2 significantly increases the affinity of human hemoglobin (HbA) for this ligand. HisE7 is also proposed to regulate the release of O2 to the solvent via a transient E7 channel. To reveal the O2 escape routes controlled by HisE7 and to evaluate its role in gating heme access, we compare simulations of O2 diffusion from the distal heme pockets of the T and R states of HbA performed with HisE7 in its open (protonated) and closed (neutral) conformations. Irrespective of HisE7's conformation, we observe the same four or five escape routes leading directly from the α- or ß-distal heme pockets to the solvent. Only 21-53% of O2 escapes occur via these routes, with the remainder escaping through routes that encompass multiple internal cavities in HbA. The conformation of the distal HisE7 controls the escape of O2 from the heme by altering the distal pocket architecture in a pH-dependent manner, not by gating the E7 channel. Removal of the HisE7 side chain in the GlyE7 variant exposes the distal pockets to the solvent, and the percentage of O2 escapes to the solvent directly from the α- or ß-distal pockets of the mutant increases to 70-88%. In contrast to O2, the dominant water route from the bulk solvent is gated by HisE7 because protonation and opening of this residue dramatically increase the rate of influx of water into the empty distal heme pockets. The occupancy of the distal heme site by a water molecule, which functions as an additional nonprotein barrier to binding of the ligand to the heme, is also controlled by HisE7. Overall, analysis of gas and water diffusion routes in the subunits of HbA and its GlyE7 variant sheds light on the contribution of distal HisE7 in controlling polar and nonpolar ligand movement between the solvent and the hemes.

Analysis of LRRN3, MEF2C, SLC22A, and P2RY12 Gene Expression in the Peripheral Blood of Patients in the Early Stages of Parkinson's Disease.

Parkinson's disease (PD) is one of the most common human neurodegenerative diseases. Belated diagnoses of PD and late treatment are caused by its elongated prodromal phase. Thus, searching for new candidate genes participating in the development of the pathological process in the early stages of the disease in patients who have not yet received therapy is relevant. Changes in mRNA and protein levels have been described both in the peripheral blood and in the brain of patients with PD. Thus, analysis of changes in the mRNA expression in peripheral blood is of great importance in studying the early stages of PD. This work aimed to analyze the changes in MEF2C, SLC22A4, P2RY12, and LRRN3 gene expression in the peripheral blood of patients in the early stages of PD. We found a statistically relevant and PD-specific change in the expression of the LRRN3 gene, indicating a disruption in the processes of neuronal regeneration and the functioning of synapses. The data obtained during the study indicate that this gene can be considered a potential biomarker of the early stages of PD.

Differential expression of Dusp1 and immediate early response genes in the hippocampus of rats, subjected to forced swim test.

The forced swim test (FST) is widely used to screen for potential antidepressant drugs and treatments. Despite this, the nature of stillness during FST and whether it resembles "depressive-like behavior" are widely debated issues. Furthermore, despite being widely used as a behavioral assay, the effects of the FST on the brain transcriptome are rarely investigated. Therefore, in this study we have investigated changes in the transcriptome of the rat hippocampus 20 min and 24 h after FST exposure. RNA-Seq is performed on the hippocampus tissues of rats 20 min and 24 h after an FST. Differentially expressed genes (DEGs) were identified using limma and used to construct gene interaction networks. Fourteen differentially expressed genes (DEGs) were identified only in the 20-m group. No DEGs were identified 24 h after the FST. These genes were used for Gene Ontology term enrichment and gene-network construction. Based on the constructed gene-interaction networks, we identified a group of DEGs (Dusp1, Fos, Klf2, Ccn1, and Zfp36) that appeared significant based on multiple methods of downstream analysis. Dusp1 appears especially important, as its role in the pathogenesis of depression has been demonstrated both in various animal models of depression and in patients with depressive disorders.

Analysis of ADORA2A, MTA1, PTGDS, PTGS2, NSF, and HNMT Gene Expression Levels in Peripheral Blood of Patients with Early Stages of Parkinson's Disease.

Parkinson's disease (PD) is a common chronic, age-related neurodegenerative disease. This disease is characterized by a long prodromal period. In this context, it is important to search for the genes and mechanisms that are involved in the development of the pathological process in the earliest stages of the disease. Published data suggest that blood cells, particularly lymphocytes, may be a model for studying the processes that occur in the brain in PD. Thus, in the present work, we performed an analysis of changes in the expression of the genes ADORA2A, MTA1, PTGDS, PTGS2, NSF, and HNMT in the peripheral blood of patients with early stages of PD (stages 1 and 2 of the Hoehn-Yahr scale). We found significant and PD-specific expression changes of four genes, i.e., MTA1, PTGS2, NSF, and HNMT, in the peripheral blood of patients with early stages of PD. These genes may be associated with PD pathogenesis in the early clinical stages and can be considered as potential candidate genes for this disease. Altered expression of the ADORA2A gene in treated PD patients may indicate that this gene is involved in processes affected by antiparkinsonian therapy.

Effective simulations of gas diffusion through kinetically accessible tunnels in multisubunit proteins: O2 pathways and escape routes in T-state deoxyhemoglobin.

The diffusion of small gases to special binding sites within polypeptide matrices pivotally defines the biochemical specificity and reactivity of proteins. We investigate here explicit O(2) diffusion in adult human hemoglobin (HbA) as a case study employing the recently developed temperature-controlled locally enhanced sampling (TLES) method and vary the parameters to greatly increase the simulation efficiency. The method is carefully validated against standard molecular dynamics (MD) simulations and available experimental structural and kinetic data on ligand diffusion in T-state deoxyHbA. The methodology provides a viable alternative approach to traditional MD simulations and/or potential of mean force calculations for: (i) characterizing kinetically accessible diffusion tunnels and escape routes for light ligands in porous proteins; (ii) very large systems when realistic simulations require the inclusion of multiple subunits of a protein; and (iii) proteins that access short-lived conformations relative to the simulation time. In the case of T-state deoxyHbA, we find distinct ligand diffusion tunnels consistent with the experimentally observed disparate Xe cavities in the α- and ß-subunits. We identify two distal barriers including the distal histidine (E7) that control access to the heme. The multiple escape routes uncovered by our simulations call for a review of the current popular hypothesis on ligand escape from hemoglobin. Larger deviations from the crystal structure during simulated diffusion in isolated α- and ß-subunits highlight the dampening effects of subunit interactions and the importance of including all subunits of multisubunit proteins to map realistic kinetically accessible diffusion tunnels and escape routes.

Analysis of PARK2 gene exon rearrangements in Russian patients with sporadic Parkinson's disease.

BACKGROUND: Deletions and duplications of single exons or exon groups account for a large proportion of the PARK2 gene mutations described in juvenile autosomal recessive Parkinson's disease (PD). METHODS: We analyzed rearrangements in exons 1 to 12 of the PARK2 gene in Russian sporadic patients with early-onset PD (EOPD) and late-onset PD (LOPD). RESULTS: The frequency of EOPD and LOPD patients carrying these mutations was 12.4% and 3.8%, respectively. The most frequent rearrangements were detected in exons 3 and 4. The odds ratio for EOPD in individuals carrying PARK2 exon deletions and duplications was 13.95 (95% confidence interval [CI], 1.846-105.46; P = .0022). In addition, we found a correlation between exon rearrangements in PARK2 and the age at onset of PD, presence of dystonia, and symmetrical course of the disease. CONCLUSIONS: Exon rearrangements in the PARK2 gene play a significant role in the pathogenesis of sporadic PD in Russian patients.

Transcriptome Profiling Reveals Differential Expression of Circadian Behavior Genes in Peripheral Blood of Monozygotic Twins Discordant for Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Investigating individuals with the most identical genetic background is optimal for minimizing the genetic contribution to gene expression. These individuals include monozygotic twins discordant for PD. Monozygotic twins have the same genetic background, age, sex, and often similar environmental conditions. The aim of this study was to carry out a transcriptome analysis of the peripheral blood of three pairs of monozygotic twins discordant for PD. We identified the metabolic process "circadian behavior" as a priority process for further study. Different expression of genes included in the term "circadian behavior" confirms that this process is involved in PD pathogenesis. We found increased expression of three genes associated with circadian behavior, i.e., PTGDS, ADORA2A, and MTA1, in twins with PD. These genes can be considered as potential candidate genes for this disease.

Challenges and Practical Solutions to MRI and Histology Matching and Measurements Using Available ImageJ Software Tools.

Traditionally histology is the gold standard for the validation of imaging experiments. Matching imaging slices and histological sections and the precise outlining of corresponding tissue structures are difficult. Challenges are based on differences in imaging and histological slice thickness as well as tissue shrinkage and alterations after processing. Here we describe step-by-step instructions that might be used as a universal pathway to overlay MRI and histological images and for a correlation of measurements between imaging modalities. The free available (Fiji is just) ImageJ software tools were used for regions of interest transformation (ROIT) and alignment using a rat brain MRI as an example. The developed ROIT procedure was compared to a manual delineation of rat brain structures. The ROIT plugin was developed for ImageJ to enable an automatization of the image processing and structural analysis of the rodent brain.

Expression Analysis of Genes Involved in Transport Processes in Mice with MPTP-Induced Model of Parkinson's Disease.

Processes of intracellular and extracellular transport play one of the most important roles in the functioning of cells. Changes to transport mechanisms in a neuron can lead to the disruption of many cellular processes and even to cell death. It was shown that disruption of the processes of vesicular, axonal, and synaptic transport can lead to a number of diseases of the central nervous system, including Parkinson's disease (PD). Here, we studied changes in the expression of genes whose protein products are involved in the transport processes (Snca, Drd2, Rab5a, Anxa2, and Nsf) in the brain tissues and peripheral blood of mice with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced models of PD. We detected changes in the expressions of Drd2, Anxa2, and Nsf at the earliest modeling stages. Additionally, we have identified conspicuous changes in the expression level of Anxa2 in the striatum and substantia nigra of mice with MPTP-induced models of PD in its early stages. These data clearly suggest the involvement of protein products in these genes in the earliest stages of the pathogenesis of PD.

Modeling Parkinson's Disease: Not Only Rodents?

Parkinson's disease (PD) is a common chronic progressive multifactorial neurodegenerative disease. In most cases, PD develops as a sporadic idiopathic disease. However, in 10%-15% of all patients, Mendelian inheritance of the disease is observed in an autosomal dominant or autosomal recessive manner. To date, mutations in seven genes have been convincingly confirmed as causative in typical familial forms of PD, i.e., SNCA, LRRK2, VPS35, PRKN, PINK1, GBA, and DJ-1. Family and genome-wide association studies have also identified a number of candidate disease genes and a common genetic variability at 90 loci has been linked to risk for PD. The analysis of the biological function of both proven and candidate genes made it possible to conclude that mitochondrial dysfunction, lysosomal dysfunction, impaired exosomal transport, and immunological processes can play important roles in the development of the pathological process of PD. The mechanisms of initiation of the pathological process and its earliest stages remain unclear. The study of the early stages of the disease (before the first motor symptoms appear) is extremely complicated by the long preclinical period. In addition, at present, the possibility of performing complex biochemical and molecular biological studies familial forms of PD is limited. However, in this case, the analysis of the state of the central nervous system can only be assessed by indirect signs, such as the level of metabolites in the cerebrospinal fluid, peripheral blood, and other biological fluids. One of the potential solutions to this problem is the analysis of disease models, in which it is possible to conduct a detailed in-depth study of all aspects of the pathological process, starting from its earliest stages. Many modeling options are available currently. An analysis of studies published in the 2000s suggests that toxic models in rodents are used in the vast majority of cases. However, interesting and important data for understanding the pathogenesis of PD can be obtained from other in vivo models. Within the framework of this review, we will consider various models of PD that were created using various living organisms, from unicellular yeast (Saccharomyces cerevisiae) and invertebrate (Nematode and Drosophila) forms to various mammalian species.

Major Depression: One Brain, One Disease, One Set of Intertwined Processes.

Major depressive disorder (MDD) is a heterogeneous disease affecting one out of five individuals and is the leading cause of disability worldwide. Presently, MDD is considered a multifactorial disease with various causes such as genetic susceptibility, stress, and other pathological processes. Multiple studies allowed the formulation of several theories attempting to describe the development of MDD. However, none of these hypotheses are comprehensive because none of them can explain all cases, mechanisms, and symptoms of MDD. Nevertheless, all of these theories share some common pathways, which lead us to believe that these hypotheses depict several pieces of the same big puzzle. Therefore, in this review, we provide a brief description of these theories and their strengths and weaknesses in an attempt to highlight the common mechanisms and relationships of all major theories of depression and combine them together to present the current overall picture. The analysis of all hypotheses suggests that there is interdependence between all the brain structures and various substances involved in the pathogenesis of MDD, which could be not entirely universal, but can affect all of the brain regions, to one degree or another, depending on the triggering factor, which, in turn, could explain the different subtypes of MDD.

SLC6A3 (DAT1) as a Novel Candidate Biomarker Gene for Suicidal Behavior.

It has been previously shown that the serotonin and dopamine neurotransmitter systems might influence the predisposition to suicidal behavior. This study aims to estimate the contribution of 11 polymorphisms in the genes SLC6A4 (5HTT), HTR1A, HTR2A, HTR1B, SLC6A3 (DAT1), DRD4, DRD2, COMT, and BDNF to suicidal behavior and severity of symptoms of depression and anxiety in the Russian population. The study was performed on 100 patients with repeated suicide attempts and 154 controls. We first found an association between SLC6A3 (DAT1) 40 bp VNTR locus and suicidal behavior. This association was significant; when using the codominant (p = 0.006), dominant (p = 0.001), overdominant (p = 0.004), and log-additive (p = 0.004) models, LL genotype played a protective role (OR = 0.48, 0.29-0.82, p = 0.005). Difference in the distribution of COMT rs4680 genotypes was significant in the codominant (p = 0.04), dominant (p = 0.013), and log-additive (p = 0.02) models, and AA genotype might protect against suicide (OR = 0.49, 0.26-0.91, p = 0.025). SLC6A4 5-HTTLPR + rs25531 locus was significant in the recessive model (p = 0.024), and also affected the severity of symptoms of depression (p = 0.044) and personal anxiety (p = 0.029). Our results suggest that allelic variants of SLC6A3, COMT, and SLC6A4 genes might be considered as risk factors for suicidal attempts.

Housekeeping Genes for Parkinson's Disease in Humans and Mice.

A critical aspect of real-time PCR is the presence of housekeeping genes (HKGs) as an internal control for the normalization of expression data for genes of interest. It is necessary to select correct HKGs in the investigation of various pathologies. Thereby, we analyzed the stability of expression of the HKGs in Parkinson's disease (PD). The work was carried out in the peripheral blood of patients with PD and in the brain tissues and peripheral blood of mice with MPTP-induced PD. As a result, Aars was the most stably expressed HKG in the mouse brain as a whole. However, different genes were more stably expressed in different parts of the brain. Polr2f was the most stably expressed in the cortex, Psmd6 was the most stably expressed in the cerebellum, and Psmd7 was the most stably expressed in the striatum and substantia nigra. HKGs were different in similar tissues of the studied organisms. Polr2f was the most stably expressed HKG in the peripheral blood of mice, whereas PSMD6 was the most stably expressed gene in humans. Thus, there is no universal HKG both for different brain tissues of one organism and for similar tissues of different organisms. Furthermore, the identified most stably expressed HKGs can be considered as such only under conditions in PD.