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.

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.

Maternal Methyl-Enriched Diet Increases DNMT1, HCN1, and TH Gene Expression and Suppresses Absence Seizures and Comorbid Depression in Offspring of WAG/Rij Rats.

The reduced expression of the HCN1 ion channel in the somatosensory cortex (SSC) and mesolimbic dopamine deficiency are thought to be associated with the genesis of spike-wave discharges (SWDs) and comorbid depression in the WAG/Rij rat model of absence epilepsy. This study aimed to investigate whether the maternal methyl-enriched diet (MED), which affects DNA methylation, can alter DNMT1, HCN1, and TH gene expression and modify absence seizures and comorbid depression in WAG/Rij offspring. WAG/Rij mothers were fed MED (choline, betaine, folic acid, vitamin B12, L-methionine, zinc) or a control diet for a week before mating, during pregnancy, and for a week after parturition. MED caused sustained suppression of SWDs and symptoms of comorbid depression in the offspring. Disease-modifying effects of MED were associated with increased expression of the DNMT1 and HCN1 genes in the SSC and hippocampus, as well as DNMT1, HCN1, and TH genes in the nucleus accumbens. No changes in gene expression were detected in the hypothalamus. The results indicate that maternal MED can suppress the genetic absence epilepsy and comorbid depression in offspring. Increased expression of the DNMT1, HCN1, and TH genes is suggested to be a molecular mechanism of this beneficial phenotypic effect.

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.

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.

Whole-Transcriptome Analysis of Dermal Fibroblasts, Derived from Three Pairs of Monozygotic Twins, Discordant for Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. In most cases, the development of the disease is sporadic and is not associated with any currently known mutations associated with PD. It is believed that changes associated with the epigenetic regulation of gene expression may play an important role in the pathogenesis of this disease. The study of individuals with an almost identical genetic background, such as monozygotic twins, is one of the best approaches to the analysis of such changes. A whole-transcriptome analysis of dermal fibroblasts obtained from three pairs of monozygotic twins discordant for PD was carried out in this work. Twenty-nine differentially expressed genes were identified in the three pairs of twins. These genes were included in seven processes within two clusters, according to the results of an enrichment analysis. The cluster with the greatest statistical significance included processes associated with the regulation of the differentiation of fat cells, the action potential, and the regulation of glutamatergic synaptic transmission. The most significant genes, which occupied a central position in this cluster, were PTGS2, SCN9A, and GRIK2. These genes can be considered as potential candidate genes for PD.

Transcriptome Profile Changes in Mice with MPTP-Induced Early Stages of Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Despite progress in the study of the molecular, genetic, and pathogenic mechanisms of PD, it is unclear which processes trigger the development of the pathology associated with PD. Models of the presymptomatic and early symptomatic stages of PD induced by MPTP have been used to analyze changes in transcriptome profile in brain tissues, to identify specific patterns and mechanisms underlying neurodegeneration in PD. The whole-transcriptome analysis in the brain tissues of the mice with MPTP-induced PD showed that striatum is involved in the pathogenesis in the earliest stages and the processes associated with vesicular transport may be altered. The expression profiles of the genes studied in the substantia nigra and peripheral blood confirm that lymphocytes from peripheral blood may reflect processes occurring in the brain. These data suggest that messenger RNA (mRNA) levels in peripheral blood may provide potential biomarkers of the neurodegeneration occurring in PD. The changes in expression at the mRNA and protein levels suggest that Snca may be involved in neurodegeneration and Drd2 may participate in the development of the compensatory mechanisms in the early stages of PD pathogenesis. Our data suggest that the brain cortex may be involved in the pathological processes in the early stages of PD, including the presymptomatic stage.