Neurogenetics

, Volume 7, Issue 3, pp 139–148

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

  • D. C. Duke
  • L. B. Moran
  • M. E. Kalaitzakis
  • M. Deprez
  • D. T. Dexter
  • R. K. B. Pearce
  • M. B. Graeber
Original Article

Abstract

There is growing evidence that dysfunction of the mitochondrial respiratory chain and failure of the cellular protein degradation machinery, specifically the ubiquitin–proteasome system, play an important role in the pathogenesis of Parkinson’s disease. We now show that the corresponding pathways of these two systems are linked at the transcriptomic level in Parkinsonian substantia nigra. We examined gene expression in medial and lateral substantia nigra (SN) as well as in frontal cortex using whole genome DNA oligonucleotide microarrays. In this study, we use a hypothesis-driven approach in analysing microarray data to describe the expression of mitochondrial and ubiquitin–proteasomal system (UPS) genes in Parkinson’s disease (PD). Although a number of genes showed up-regulation, we found an overall decrease in expression affecting the majority of mitochondrial and UPS sequences. The down-regulated genes include genes that encode subunits of complex I and the Parkinson’s-disease-linked UCHL1. The observed changes in expression were very similar for both medial and lateral SN and also affected the PD cerebral cortex. As revealed by “gene shaving” clustering analysis, there was a very significant correlation between the transcriptomic profiles of both systems including in control brains. Therefore, the mitochondria and the proteasome form a higher-order gene regulatory network that is severely perturbed in Parkinson’s disease. Our quantitative results also suggest that Parkinson’s disease is a disease of more than one cell class, i.e. that it goes beyond the catecholaminergic neuron and involves glia as well.

Keywords

Alpha-synuclein Gene shaving Microarrays Oxidative stress Ubiquitin–proteasome system 

Supplementary material

10048_2006_33_MOESM1_ESM.gif (90 kb)
Supplemental Figure 1

Schematic of the mitochondrial electron transport chain illustrating the components of this pathway that are differentially expressed in PD SN http://www.GenMapp.org)

10048_2006_33_MOESM2_ESM.gif (54 kb)
Supplemental Figure 2

Schematic of the ubiquitin–proteasome system illustrating the components of this pathway that are differentially expressed in PD SN (http://www.GenMapp.org)

10048_2006_33_MOESM3_ESM.gif (14 kb)
Supplemental Figure 3

The first 15 subjects are PD cases; the last eight are controls. The X-axis indicates the pathway expression values, which represents the individuals’ contribution to gene expression variability within the cluster. Upper panel: gene shaving analysis of the 74 mitochondrial transcripts that were up-regulated in PD SNm extracted a cluster that consisted of six probes encoding three genes; TXNIP, MAOA and PDK4. This figure shows that there is a clear up-regulation of expression of these genes in the PD cases; however, PD8, PD9, PD11 and PD12 have expression profiles more like controls, based on this cluster. Lower panel: gene shaving analysis of the 24 UPS transcripts that were up-regulated in PD SNm reveals a cluster of three probes encoding 2 genes; SMURF2 and UHRF1. This figure shows that this analysis reveals a different pattern of individual variation, with half of the PD group having very high expression of this gene cluster and half looking more like the controls

10048_2006_33_MOESM4_ESM.gif (14 kb)
Supplemental Figure 4

Figure shows the result of gene shaving analysis using a dopamine marker gene filter. There is a general down-regulation of gene expression in the PD group. However, this expression pattern is different from that observed in the other gene shaving analyses, indicating those results are not primarily due to a lack of dopamine neurons in the SN

10048_2006_33_MOESM5_ESM.pdf (51 kb)
Supplemental Table 1Mitochondrial genes that are up-regulated in PD SNm compared to controls (p>0.01). False discovery rate (FDR) was the multiple-comparisons test used. ‘Yes’ in the last column indicates that the transcript passed this multiple-comparisons test. *Indicates that the transcript was also up-regulated in PD lateral nigra (PDF 52 kb)
10048_2006_33_MOESM6_ESM.pdf (50 kb)
Supplemental Table 2Mitochondrial genes that are up-regulated in PD SNl compared to controls (p>0.01) that were not also up-regulated in PD SNm. False discovery rate (FDR) was the multiple comparisons test used. ‘Yes’ in the last column indicates that the transcript passed this multiple-comparisons test (PDF 52 kb)
10048_2006_33_MOESM7_ESM.pdf (60 kb)
Supplemental Table 3Mitochondrial genes are down-regulated in PD SNm compared to controls (p>0.01). False Discovery Rate (FDR) was the multiple-comparisons test used. ‘Yes’ in the last column indicates that the transcript passed this multiple-comparisons test. *Indicates that the transcript was also down-regulated in PD lateral nigra (PDF 61 kb)
10048_2006_33_MOESM8_ESM.pdf (46 kb)
Supplemental Table 4Mitochondrial genes that are down-regulated in PD SNl compared to controls (p>0.01) that were not also down-regulated in PD SNm. False Discovery Rate (FDR) was the multiple-comparisons test used. ‘Yes’ in the last column indicates that the transcript passed this multiple-comparisons test (PDF 47 kb)
10048_2006_33_MOESM9_ESM.pdf (47 kb)
Supplemental Table 5Ubiquitin–proteasome genes that were up-regulated in PD SNl compared to controls (p>0.01), but not in SNm. False Discovery Rate (FDR) was the multiple-comparisons test used. ‘Yes’ in the last column indicates that the transcript passed this multiple-comparisons test (PDF 48 kb)
10048_2006_33_MOESM10_ESM.pdf (53 kb)
Supplemental Table 6Ubiquitin–proteasome genes that are down-regulated in PD SNm compared to controls (p>0.01). False Discovery Rate (FDR) was the multiple-comparisons test used. ‘Yes’ in the last column indicates that the transcript passed this multiple-comparisons test. *Indicates that these transcripts were down-regulated in SNl as well (PDF 55 kb)
10048_2006_33_MOESM11_ESM.pdf (45 kb)
Supplemental Table 7Ubiquitin–proteasome genes that are down-regulated in PD SNl compared to controls (p>0.01), but not in SNm. False Discovery Rate (FDR) was the multiple-comparisons test used. ‘Yes’ in the last column indicates that the transcript passed this multiple-comparisons test (PDF 46 kb)
10048_2006_33_MOESM12_ESM.pdf (55 kb)
Supplemental Table 8Gene shaving filters and clusters (PDF 56 kb)

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • D. C. Duke
    • 1
  • L. B. Moran
    • 1
  • M. E. Kalaitzakis
    • 1
  • M. Deprez
    • 2
  • D. T. Dexter
    • 3
  • R. K. B. Pearce
    • 1
  • M. B. Graeber
    • 1
  1. 1.Department of NeuropathologyImperial College London and Hammersmith,Hospitals TrustLondonUK
  2. 2.Laboratory of NeuropathologyUniversity Hospital,University of LiègeLiègeBelgium
  3. 3.Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental HealthImperial College LondonLondonUK

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