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Lipid pathway alterations in Parkinson's disease primary visual cortex.

Cheng D, Jenner AM, Shui G, Cheong WF, Mitchell TW, Nealon JR, Kim WS, McCann H, Wenk MR, Halliday GM, Garner B - PLoS ONE (2011)

Bottom Line: We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05).Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Research Australia, Sydney, New South Wales, Australia.

ABSTRACT

Background: We present a lipidomics analysis of human Parkinson's disease tissues. We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.

Methodology/principal findings: Using liquid chromatography mass spectrometry lipidomics techniques for an initial screen of 200 lipid species, significant changes in 79 sphingolipid, glycerophospholipid and cholesterol species were detected in the visual cortex of Parkinson's disease patients (n = 10) compared to controls (n = 10) as assessed by two-sided unpaired t-test (p-value <0.05). False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05). By contrast, changes in 17 and 12 lipid species were identified in the Parkinson's disease amygdala and anterior cingulate cortex, respectively, compared to controls; none of which remained significant after false discovery rate analysis. Using gas chromatography mass spectrometry techniques, 6 out of 7 oxysterols analysed from both non-enzymatic and enzymatic pathways were also selectively increased in the Parkinson's disease visual cortex. Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.

Conclusions/significance: The data indicate that changes in lipid metabolism occur in the Parkinson's disease visual cortex in the absence of obvious pathology. This suggests that normalization of lipid metabolism and/or oxidative stress status in the visual cortex may represent a novel route for treatment of non-motor symptoms, such as visual hallucinations, that are experienced by a majority of Parkinson's disease patients.

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Simplified scheme of relevant glycerophospholipids and related genes assessed in this study.A simplified schematic diagram of relevant glycerophospholipids and related genes assessed in this study. The lipids in the boxes with black borders were analysed in the present study. Phosphatidylcholine (PC); phosphatidic acid (PA); phosphatidylinositol PI; phosphatidylserine PS; phosphatidylethanolamine (PE); diacylglycerol (DAG); cytidine diphosphate-diacylglycerol (CDP-DAG); cytidinediphosphate-choline (CDP-Choline); cytidinediphosphate-ethanolamine (CDP-Etn); phosphocholine cytidylytransferase 1a (PCYT1A); phosphatidic acid phosphatase 2a (PPAP2A); phosphatidic acid phosphatase 2B (PPAP2B); phosphatidylserine synthase I (PtDSS1).
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pone-0017299-g006: Simplified scheme of relevant glycerophospholipids and related genes assessed in this study.A simplified schematic diagram of relevant glycerophospholipids and related genes assessed in this study. The lipids in the boxes with black borders were analysed in the present study. Phosphatidylcholine (PC); phosphatidic acid (PA); phosphatidylinositol PI; phosphatidylserine PS; phosphatidylethanolamine (PE); diacylglycerol (DAG); cytidine diphosphate-diacylglycerol (CDP-DAG); cytidinediphosphate-choline (CDP-Choline); cytidinediphosphate-ethanolamine (CDP-Etn); phosphocholine cytidylytransferase 1a (PCYT1A); phosphatidic acid phosphatase 2a (PPAP2A); phosphatidic acid phosphatase 2B (PPAP2B); phosphatidylserine synthase I (PtDSS1).

Mentions: To understand the underlying mechanisms that may contribute to regional changes in glycerophospholipid metabolism in PD, we assessed the expression of a selection of relevant genes in the full sample cohort by qRT-PCR (as depicted in Figure 6). Of the genes investigated, the data indicated that PCYT1A was significantly up-regulated in the PD VC. This gene is important for the production of CDP-choline which is required to synthesise PC (Fig. 6). Interestingly, not all species of PC were increased in the PD VC and this may be due to conversion of specific molecular species of PC to PS. Consistent with this, PS levels were significantly increased in the PD VC and there was a non-significant trend for a 5-fold increase in the expression of the PTDSS1 gene that encodes for the enzyme required to catalyse this reaction (Fig. 7). Although DAG (classified here as a neutral lipid but also a crucial intermediate in glycerophospholipid synthesis, Fig. 6) levels were increased in the PD VC (Fig. 3), expression of two genes important for the synthesis of DAG from PA (PPAP2A and PPAP2B) were not significantly changed; although a trend for up-regulation was detected in the VC but not in the ACC or AMY (Fig. 7). Overall, the data point towards subtle modulation of the glycerophospholipid biosynthetic pathway to selectively modify glycerophospholipid profiles in the PD VC. The induction of the PCYT1A gene in the PD VC suggests that at least part of this change in lipid profile is transcriptionally regulated.


Lipid pathway alterations in Parkinson's disease primary visual cortex.

Cheng D, Jenner AM, Shui G, Cheong WF, Mitchell TW, Nealon JR, Kim WS, McCann H, Wenk MR, Halliday GM, Garner B - PLoS ONE (2011)

Simplified scheme of relevant glycerophospholipids and related genes assessed in this study.A simplified schematic diagram of relevant glycerophospholipids and related genes assessed in this study. The lipids in the boxes with black borders were analysed in the present study. Phosphatidylcholine (PC); phosphatidic acid (PA); phosphatidylinositol PI; phosphatidylserine PS; phosphatidylethanolamine (PE); diacylglycerol (DAG); cytidine diphosphate-diacylglycerol (CDP-DAG); cytidinediphosphate-choline (CDP-Choline); cytidinediphosphate-ethanolamine (CDP-Etn); phosphocholine cytidylytransferase 1a (PCYT1A); phosphatidic acid phosphatase 2a (PPAP2A); phosphatidic acid phosphatase 2B (PPAP2B); phosphatidylserine synthase I (PtDSS1).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3046155&req=5

pone-0017299-g006: Simplified scheme of relevant glycerophospholipids and related genes assessed in this study.A simplified schematic diagram of relevant glycerophospholipids and related genes assessed in this study. The lipids in the boxes with black borders were analysed in the present study. Phosphatidylcholine (PC); phosphatidic acid (PA); phosphatidylinositol PI; phosphatidylserine PS; phosphatidylethanolamine (PE); diacylglycerol (DAG); cytidine diphosphate-diacylglycerol (CDP-DAG); cytidinediphosphate-choline (CDP-Choline); cytidinediphosphate-ethanolamine (CDP-Etn); phosphocholine cytidylytransferase 1a (PCYT1A); phosphatidic acid phosphatase 2a (PPAP2A); phosphatidic acid phosphatase 2B (PPAP2B); phosphatidylserine synthase I (PtDSS1).
Mentions: To understand the underlying mechanisms that may contribute to regional changes in glycerophospholipid metabolism in PD, we assessed the expression of a selection of relevant genes in the full sample cohort by qRT-PCR (as depicted in Figure 6). Of the genes investigated, the data indicated that PCYT1A was significantly up-regulated in the PD VC. This gene is important for the production of CDP-choline which is required to synthesise PC (Fig. 6). Interestingly, not all species of PC were increased in the PD VC and this may be due to conversion of specific molecular species of PC to PS. Consistent with this, PS levels were significantly increased in the PD VC and there was a non-significant trend for a 5-fold increase in the expression of the PTDSS1 gene that encodes for the enzyme required to catalyse this reaction (Fig. 7). Although DAG (classified here as a neutral lipid but also a crucial intermediate in glycerophospholipid synthesis, Fig. 6) levels were increased in the PD VC (Fig. 3), expression of two genes important for the synthesis of DAG from PA (PPAP2A and PPAP2B) were not significantly changed; although a trend for up-regulation was detected in the VC but not in the ACC or AMY (Fig. 7). Overall, the data point towards subtle modulation of the glycerophospholipid biosynthetic pathway to selectively modify glycerophospholipid profiles in the PD VC. The induction of the PCYT1A gene in the PD VC suggests that at least part of this change in lipid profile is transcriptionally regulated.

Bottom Line: We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05).Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Research Australia, Sydney, New South Wales, Australia.

ABSTRACT

Background: We present a lipidomics analysis of human Parkinson's disease tissues. We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.

Methodology/principal findings: Using liquid chromatography mass spectrometry lipidomics techniques for an initial screen of 200 lipid species, significant changes in 79 sphingolipid, glycerophospholipid and cholesterol species were detected in the visual cortex of Parkinson's disease patients (n = 10) compared to controls (n = 10) as assessed by two-sided unpaired t-test (p-value <0.05). False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05). By contrast, changes in 17 and 12 lipid species were identified in the Parkinson's disease amygdala and anterior cingulate cortex, respectively, compared to controls; none of which remained significant after false discovery rate analysis. Using gas chromatography mass spectrometry techniques, 6 out of 7 oxysterols analysed from both non-enzymatic and enzymatic pathways were also selectively increased in the Parkinson's disease visual cortex. Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.

Conclusions/significance: The data indicate that changes in lipid metabolism occur in the Parkinson's disease visual cortex in the absence of obvious pathology. This suggests that normalization of lipid metabolism and/or oxidative stress status in the visual cortex may represent a novel route for treatment of non-motor symptoms, such as visual hallucinations, that are experienced by a majority of Parkinson's disease patients.

Show MeSH
Related in: MedlinePlus