The progressive degradation of the nigrostriatal system leads to the development of Parkinson’s disease (PD). The synthesis of dopamine, the neurotransmitter of the nigrostriatal system, depends on the rate-limiting enzyme, tyrosine hydroxylase (TH). In this study, we evaluated the synthesis of dopamine during periods of neurodegradation and neuroplasticity in the nigrostriatal system on a model of the early clinical stage of PD. It was shown that the concentration of dopamine correlated with activity of TH, while TH activity did not depend on total protein content either in the SN or in the striatum. Both during the period of neurodegeneration and neuroplasticity, TH activity in SN was determined by the content of P19-TH, and in the striatum it was determined by P31-TH and P40-TH (to a lesser extent). The data obtained indicate a difference in the regulation of dopamine synthesis between DA-neuron bodies and their axons, which must be considered for the further development of symptomatic pharmacotherapy aimed at increasing TH activity.

Valosin-containing human protein (VCP) or p97 performs enzyme functions associated with the maintenance of protein homeostasis and control of protein quality. Disruption of its normal functioning might be associated with the development of Parkinson’s disease (PD). Tissues of mice with toxin-induced presymptomatic and early symptomatic stages of PD, as well as 52 treated and untreated patients with newly diagnosed PD and nine patients with a “predicted” form of PD, were investigated. Significant changes in Vcp gene expression were observed in almost all studied mouse tissues. A significant decrease in VCP expression specific for PD was also detected at both the late preclinical and the early clinical stages of PD in untreated patients. Thus, a decrease in VCP expression is important for changes in the function of the nervous system at early stages of PD. Analysis of changes in VCP expression in all patients with PD and in Vcp in the peripheral blood of mice used as models of PD revealed significant decreases in expression specific for PD. These data suggest that a decrease in the relative levels of VCP mRNA might serve as a biomarker for the development of pathology at the early clinical and preclinical stages of human PD.

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.