VCP expression decrease as a biomarker of preclinical and early clinical stages of Parkinson's disease

Abstract

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.

Figure 1

Network demonstrating the main processes involving VCP and SNCA in the pathogenesis of PD. Processes are highlighted in yellow, genes studied are in red, disease (PD) is in purple, and cells (neuron) are in blue. The colored arrows indicate the relationship between the gene and the object: regulatory pathways are in gray, genetic changes are in burgundy, and arrows marked with + indicate positive links (by Pathway Studio v.12.1.0.9).

Figure 2

The relative levels of the Vcp gene expression. A The relative levels of mRNA and protein of the Vcp gene in the substantia nigra (S.Nigra) and striatum of mice with MPTP-induced models of PD. B The relative levels of Vcp mRNA in the substantia nigra and striatum of mice with models of PD induced by MPTP. Black line shows levels of Vcp in the control group taken as 1. For clarity of the data presentation, a decrease of expression is presented as “−1/N-fold”.