Human Postmortem Pd Subjects

The study of post-mortem tissue is relatively difficult (59,60) and the availability of the tissue is scarce. Thus only very recently several groups have managed to conduct gene expression studies in human PD patients. However, comparison of results is difficult since each group has different SN tissue preparations. The ideal programme would be an international agreement to use exactly similar regions and specifically SNpc, where melanin-containing dopamine neurons die. The first study on gene expression profiles in the SN and adjacent midbrain tissues of two normal subjects using SAGE technique revealed 402 SN genes that lay within 5 large genomic linkage regions (61). Genes such as transcription elongation factor A (SII)-like 1, apolipoprotein J, ferritin heavy polypeptide 1 and beta-2-microglobulin were some of the 20 most highly expressed SAGE tags in the pooled SN libraries. But in this study no comparison to PD tissue was conducted.

Our group for the first time was able to show the specific expression patterns of genes in post-mortem SNpc in sporadic PD using Affymetrix GeneChip arrays (62). This study identified decreased expression of 68 genes and elevation of 69 genes in SN of PD patients compared to controls. Classification into functional groups revealed that genes related to signal transduction, protein degradation (e.g. ubiquitin-proteasome subunits), dopaminergic transmission/metabolism, iron transport, protein modification/phosphorylation, and energy pathways/glycolysis functional classes were down-regulated. Decreased expressions of 5 subunits of the ubiquitin-proteasome system, SKP1A, a member of the SCF (E3) ubiquitin ligase complex, and chaperone HSC-70, which can lead to a wide impairment in the function of an entire repertoire of proteins, were found in PD patients. Genes involved in adhesion/cytoskeleton, extracellular matrix components, cell cycle, protein modification/phosphorylation, protein metabolism and transcription, and inflammation/hypoxia (e.g. key iron and oxygen sensor EGLN1) were up-regulated in PD SN. These results have shed light on the molecular mechanism implicated in PD and may explain evidence indicating accumulation of misfolded proteins and aggregation of ubiquitinated substrates in the Lewy body, such as a-synuclein, sinphylin 1 and tyrosine hydroxylase or in neuro-fibrillary tangles, such as tau-proteins and amyloid plaques with amyloid-beta in both genetic and sporadic diseases.

Three consecutive publications showed similar results as in our original report (63-65). The first group compared between mesencephalic dopaminergic neurons containing Lewy bodies and neurons not containing Lewy bodies in PD patients using DD (64). About 64 ESTs were found to be altered in the dopaminergic Lewy body containing neurons. One of the genes found to be up-regulated in the Lewy body containing neurons is the ubiquitinating specific peptidase 8 (USP8). This, as in the previous study, points to the involvement of protein misfolding and degradation in PD. The stress 70 protein chaperone, microsome-associated 60 kDa (STCH) showed down-regulation in the Lewy body containing neurons. This protein is known to be a "core ATPase" encoding Hsp70-like gene, which was also shown to be altered in the first chip analysis.

Zhang et al. (65) studied gene expression alterations in three different brain regions of PD patients, the SN, putamen and area 9 using the Affymetrix GeneChip arrays. Striking similarity to our results was found in all three brain regions. Up-regulation of heat shock 27 kDa protein 1 (HspBl) mRNA and down-regulation of the NADH dehydrogenase (ubiquinone) Fe-S protein1 (NDUFS1) mRNA, SKP1 family tetrameriza-tion domain, synuclein and of synaptosomal-associated protein 25 kDa (SNAP25) were observed.

Hauser et al. (63) compared SN gene expression in four different groups using Affymetrix GeneChip arrays: PD, controls, progressive supernuclear palsy and fronto-temporal dementia with parkinsonism. Here, they found 142 genes were significantly altered between PD cases and controls, 96 genes between progressive supernuclear palsy and frontotemporal dementia with parkinsonism to controls. There were 12 genes common to all disorders. Again, as in all the three studies four pathways were shown to be altered in PD SN: chaperones, ubiquitination, vesicle trafficking, and nuclear-encoded mitochondrial genes.

These new findings may help to develop a new hypothesis concerning the aetiology of the disease and may provide a better diagnostic tool to the clinicians. We tried to collect these findings into a cascade of events, which may show the relations to OS between these gene alterations and cell death (Figs. 1 and 2).

Degraded protein

Fig. 1. For legend see opposite page.

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