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Abstract
BackgroundParkinson's disease (PD) is the most common neurodegenerative disorder involving the motor system. Although not being the only region involved in PD, affection of the substantia nigra and its projections is responsible for some of the most debilitating features of the disease. To further advance a comprehensive understanding of nigral pathology, we conducted a tissue based comparative proteome study of healthy and diseased human substantia nigra.ResultsThe gross number of differentially regulated proteins in PD was 221. In total, we identified 37 proteins, of which 16 were differentially expressed. Identified differential proteins comprised elements of iron metabolism (H-ferritin) and glutathione-related redox metabolism (GST M3, GST P1, GST O1), including novel redox proteins (SH3BGRL). Additionally, many glial or related proteins were found to be differentially regulated in PD (GFAP, GMFB, galectin-1, sorcin), as well as proteins belonging to metabolic pathways sparsely described in PD, such as adenosyl homocysteinase (methylation), aldehyde dehydrogenase 1 and cellular retinol-binding protein 1 (aldehyde metabolism). Further differentially regulated proteins included annexin V, beta-tubulin cofactor A, coactosin-like protein and V-type ATPase subunit 1. Proteins that were similarly expressed in healthy or diseased substantia nigra comprised housekeeping proteins such as COX5A, Rho GDI alpha, actin gamma 1, creatin-kinase B, lactate dehydrogenase B, disulfide isomerase ER-60, Rab GDI beta, methyl glyoxalase 1 (AGE metabolism) and glutamine synthetase. Interestingly, also DJ-1 and UCH-L1 were expressed similarly. Furthermore, proteins believed to serve as internal standards were found to be expressed in a constant manner, such as 14-3-3 epsilon and hCRMP-2, thus lending further validity to our results.ConclusionUsing an approach encompassing high sensitivity and high resolution, we show that alterations of SN in PD include many more proteins than previously thought. The results point towards a heterogeneous aetiopathogenesis of the disease, including alterations of GSH-related proteins as well as alterations of proteins involved in retinoid metabolism, and they indicate that proteins involved in familial PD may not be differentially regulated in idiopathic Parkinson's disease.
Highlights
Parkinson's disease (PD) is the most common neurodegenerative disorder involving the motor system
Many glial or related proteins were found to be differentially regulated in PD (GFAP, glial maturation factor beta (GMFB), galectin-1, sorcin), as well as proteins belonging to metabolic pathways sparsely described in PD, such as adenosyl homocysteinase, aldehyde dehydrogenase 1 and cellular retinol-binding protein 1
The results point towards a heterogeneous aetiopathogenesis of the disease, including alterations of GSH-related proteins as well as alterations of proteins involved in retinoid metabolism, and they indicate that proteins involved in familial PD may not be differentially regulated in idiopathic Parkinson's disease
Summary
Parkinson's disease (PD) is the most common neurodegenerative disorder involving the motor system. All chemical models of PD, including 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) [6] and rotenone [7], lead to an increase of oxidative stress as well as mitochondrial and proteasome dysfunction Still, they cause an acute and selective loss of dopaminergic neurons, which might not exactly mirror the pathology involved in idiopathic PD. While genetic forms of the disease involving mutations in genes for proteins like alpha-synuclein [9,10], parkin [11] and ubiquitin carboxyterminal hydrolase L1 (UCH-L1) [12], have shed substantial light on possible pathomechanisms such as failure of the ubiquitine-proteasome-system, these seem to account for a small minority of cases only [13] All of these aetiologic mechanisms have been reported by numerous groups using a wide array of methods, but still it has not been possible to convert these advances in knowledge into therapeutic strategies. It has been suggested recently that research on PD should move away from traditional targets and methods [14]
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