Analysis of the Neuroproteome Associated With Cell Therapy After Intranigral Grafting in a Mouse Model of Parkinson Disease

Advances in large-scale proteomics analysis have been very useful in understanding pathogenesis of diseases and elaborating therapeutic strategies. Proteomics has been employed to study Parkinson’s disease (PD), however, sparse studies reported proteome investigation after cell therapy approaches. In this study, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) and systems biology to identify differentially expressed proteins in a translational mouse model of PD after cell therapy. Proteins were extracted from five nigrostriatal-related brain regions of mice previously lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN). Protein expression was compared in non-grafted brain to 1 and 7 days after intranigral grafting of E12.5 embryonic ventral mesencephalon (VM). We found a total of 277 deregulated proteins after transplantation, which are enriched for lipid metabolism, oxidative phosphorylation and PD; thus, confirming that our animal model is similar to human PD and that the presence of grafted cells modulates the expression of these proteins. Notably, 7 proteins (Acta1, Atp6v1e1, Eci3, Lypla2, Pip4k2a, Sccpdh and Sh3gl2) were commonly downregulated after engraftment in all studied brain regions. These proteins are known to be involved in the formation of lipids and recycling of dopamine (DA) vesicle at the synapse. Moreover, intranigral transplantation of VM cells decreased the expression of proteins related to oxidative stress, especially in the nigrostriatal pathway containing the DA grafted neurons. In the same regions, an upregulation of several proteins including alpha-synuclein and tyrosine hydroxylase were observed, whereas expression of tetraspanin 7 was shut down. Overall, these results suggest that intranigral transplantation of VM tissue in an animal model of PD may induce a decrease of oxidative stress in the nigrostriatal pathway and a restoration of the machinery of neurotransmitters, particularly dopamine release to promote DA transmission through a decrease of D2 dopamine receptors endocytosis. Identification of new mechanistic elements involved in the nigrostriatal reconstruction process, using translational animal models and systems biology, is a promising approach to enhance the repair of this pathway in PD patients undergoing cell therapy.