Proteomic Studies Of Experimental Parkinson's Disease Induced By 6-OHDA In Rats

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder,characterized by the degeneration of dopaminergic neurons and dopaminergic neuritesfrom substantia nigra and striatum, and by the formation of eosinophilic inclusion, Lewybody in survial dopaminergic neurons.The transmitter of dopamine considerablydecreases, leading to functional disturbance of central and automatic nervous system.Thepathogenesis of PD is very complicated. Many factors take part in it. That is, manyproteins have synergistic effects on dopaminergic neurons and determine theirfate.Studies about PD based on animal models have being rapidly developed.Paralleling with the experimental models of PD, the experimental methods of PD, atlevels of molecule, cell and integerity, combined function with morphous, have beendeveloped. Among these methods, proteomics has become one of the most importantmethod today. It abandoned the traditional research pattern through which a single proteinis studied independently. For the first time to study protein composition and regularity inthe cells as a whole becomes possible. The new method is becoming very important forstudying neurodegenerative diseases. From recognition of structural proteins to evaluationof differential expression of functional proteins, this technique develops very fast. Thoughstudies on PD have made large progress, the mechanism of PD, the early diagnosis andthe effective treatment need to be explored urgently. With the development of proteomicstechnique, the intervention of proteomics, especially comparative proteomics, bringsabout new hope in these fields. Specific proteins closely related with PD can be found byproteomic study, it will facilitate the early diagnosis of PD and provid the treatmenttargets of PD.To deeply explore the mechanism of PD, PD model induced by 6-OHDA in Wistarrats, in line with the international standard,was established. The expression of proteins instriatum of this model were analyzed using the technique of two dimensional differentialgel electrophoresis(DIGE) and mass spectrometry(MS).In our present study, six proteins were found to be differentially expressed andidentified by DIGE and MS respectively. Among these, 4 proteins (ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), Peroxiredoxinâ…¡(Prxâ…¡), glutamine synthetase (GS)and heat shock protein 90? (HSP90?)) increased significantly and 2 protein (mitochondrialcis-aconitase (ACO2) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH))decreased significantly.For the first time, our study found that the expression of UCH-L1 significantlyincreased in striatum of PD model induced by 6-OHDA in Wistar rats. The resultcoincides with that at the level of mRNA. Increased UCH-L1 may help dopaminergicneurons to eliminate unwanted proteins, delay the accumulation of unwanted proteins.The high level expression of UCH-L1 may be protective in this experimental animalmodel.For the first time, our study found that the expression of Prx â…¡ significantlyincreased in striatum of PD model induced by 6-OHDA in Wistar rats. High levelexpression of Prx â…¡ suggests the mechanism of neuroprotection against stress inexperimental animal. It suggests that Prx â…¡ might be a potential target which can becontroled in order to prevent neurons from oxidative stress.For the first time, our study found that the expression of GS significantly increasedin striatum of PD model induced by 6-OHDA in Wistar rats. Up-regulation of GS may bea marker of protective compensatory response when nigra-striatum system had beendamaged by 6-OHDA. Regulation of GS activity may keep the dynamic balance ofGlu-Gln circulation and keep neurons from the exitotoxicity of Glu.For the first time, our study found that the expression of The study first found theexpression of HSP90? significantly increased in striatum of PD model induced by6-OHDA in Wistar rats.The result is consistent with that PD model induced by MPTP inmice. The increased expression of HSP90? in striatum may represent the resistance toapoptosis of neurons under toxic stress. HSP90? may be a potential target to stop theprogress of apoptosis and promote neuroprotective effects.For the first time, our study found that the expression of ACO2 significantlydecreased in striatum of PD model induced by 6-OHDA in Wistar rats. The result is inaccord with these in PD model induced by MPTP in mice and in human PD. The downregulation of ACO2 is a important marker of functional disturbance of mitochondria. Itsupport the idea that functional disturbance of mitochondria may play a crucial role in PD.Inhibiting the down regulation of ACO2 may interrupt the progress of degeneration ofdopaminergic neurons.For the first time, our study found that the expression of GAPDH significantlydecreased in striatum of PD model induced by 6-OHDA in Wistar rats. Our result isdifferent from these in models induced by MPTP/MPP+. The down regulation of GAPDHmay represent an anti-apoptosis mechanism in experimental animal. It may be in favourof interrupting apoptosis to manipulate GAPDH. GAPDH may be other target of PDtreatment.Monitoring the changes of above 6 proteins simultaneously by proteomic techniquesmay offer a new objective index system to screen and evaluate medicines against PDthrough the PD model induced by 6-OHDA.