Since the 1980s, the concept of dopamine-rich brain centers as clusters of only dopaminergic neurons has been fundamentally revised. It has been shown that, in addition to dopaminergic neurons, most of these centers contain neurons expressing one of the enzymes of dopamine synthesis: tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). We have obtained convincing evidence that in rats, the hypothalamic periventricular nucleus (PeVN) is one of the largest dopamine-rich centers, containing dopaminergic and monoenzymatic neurons. Indeed, using double immunostaining for TH and AADC, the PeVN was shown to contain almost three thousand dopaminergic and monoenzymatic neurons. According to high-performance liquid chromatography, PeVN contains L-DOPA and dopamine, which, apparently, are synthesized in monoenzymatic TH neurons and bienzymatic neurons, respectively. According to confocal microscopy, neurons (cell bodies, fibers), which were immunopositive only to TH, only to AADC, or both, are in close topographic relationships with each other and with the 3rd ventricle. These data suggest the mutual regulation of the neurons, as well as the delivery of dopamine and L-DOPA to the third ventricle, which is confirmed by their detection in the cerebrospinal fluid. Thus, evidence has been obtained that PeVN is one of the largest dopamine-rich centers of the brain, containing dopaminergic and monoenzymatic neurons.

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.

The aim of this work was to detect changes in proteasome pools of brain parts of August rats with monoamine metabolism violations in comparison with that of control Wistar rats. To reveal active proteasome structures, a method of native electrophoresis for the analysis of crude tissue fractions was developed. By means of this method and following Western blotting, the most pronounced changes in reorganization of proteasome structures were detected in proteasome pool of the brain cortex of August rats. Main findings are the enhanced expression of immune proteasome subtypes containing proteolytic subunit LMP2 and activator PA28αβ as well as immune proteasome subtypes containing proteolytic subunit LMP7 and activator PA700 and simultaneously decreased expression of subtypes with subunit LMP2 and activator PA700 in the brain cortex of August rats compared to that of Wistar rats. These results were indirectly confirmed by SDS PAGE method followed by Western blotting, which showed the increased quantities of immune subunits and proteasome activators in the brain cortex of August rats compared to that of Wistar rats. Immune proteasomes were revealed by immunohistochemistry in neurons, but not in glial cells of August and Wistar rat cortex. The detected reorganization of proteasome pools is likely to be important for production of special peptides to provide the steady interaction between neurons and adaptation of central nervous system to conditions caused by monoamine metabolism deviations.

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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.