Dataset Information

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

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.

SUBMITTER: Cheng D

PROVIDER: S-EPMC3046155 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Cheng Danni D Jenner Andrew M AM Shui Guanghou G Cheong Wei Fun WF Mitchell Todd W TW Nealon Jessica R JR Kim Woojin S WS McCann Heather H Wenk Markus R MR Halliday Glenda M GM Garner Brett B

PloS one 20110228 2

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>Using liquid chromatography mass spectrometry lipidomics techniques for ...[more]

PMID: 21387008

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Project description:Many genetic risk factors for Parkinson's disease have lipid-related functions and lipid-modulating drugs such as statins may be protective against Parkinson's disease. Moreover, the hallmark Parkinson's disease pathological protein, α-synuclein, has lipid membrane function and pathways dysregulated in Parkinson's disease such as the endosome-lysosome system and synaptic signalling rely heavily on lipid dynamics. Despite the potential role for lipids in Parkinson's disease, most research to date has been protein-centric, with large-scale, untargeted serum and CSF lipidomic comparisons between genetic and idiopathic Parkinson's disease and neurotypical controls limited. In particular, the extent to which lipid dysregulation occurs in mutation carriers of one of the most common Parkinson's disease risk genes, LRRK2, is unclear. Further, the functional lipid pathways potentially dysregulated in idiopathic and LRRK2 mutation Parkinson's disease are underexplored. To better determine the extent of lipid dysregulation in Parkinson's disease, untargeted high-performance liquid chromatography-tandem mass spectrometry was performed on serum (n = 221) and CSF (n = 88) obtained from a multi-ethnic population from the Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium. The cohort consisted of controls, asymptomatic LRRK2 G2019S carriers, LRRK2 G2019S carriers with Parkinson's disease and Parkinson's disease patients without a LRRK2 mutation. Age and sex were adjusted for in analyses where appropriate. Approximately 1000 serum lipid species per participant were analysed. The main serum lipids that distinguished both Parkinson's disease patients and LRRK2 mutation carriers from controls included species of ceramide, triacylglycerol, sphingomyelin, acylcarnitine, phosphatidylcholine and lysophosphatidylethanolamine. Significant alterations in sphingolipids and glycerolipids were also reflected in Parkinson's disease and LRRK2 mutation carrier CSF, although no correlations were observed between lipids identified in both serum and CSF. Pathway analysis of altered lipid species indicated that sphingolipid metabolism, insulin signalling and mitochondrial function were the major metabolic pathways dysregulated in Parkinson's disease. Importantly, these pathways were also found to be dysregulated in serum samples from a second Parkinson's disease cohort (n = 315). Results from this study demonstrate that dysregulated lipids in Parkinson's disease generally, and in LRRK2 mutation carriers, are from functionally and metabolically related pathways. These findings provide new insight into the extent of lipid dysfunction in Parkinson's disease and therapeutics manipulating these pathways may be beneficial for Parkinson's disease patients. Moreover, serum lipid profiles may be novel biomarkers for both genetic and idiopathic Parkinson's disease.

Project description:In the cat primary visual cortex, it is accepted that neurons optimally responding to similar stimulus orientations are clustered in a column extending from the superficial to deep layers. The cerebral cortex is, however, folded inside a skull, which makes gyri and fundi. The primary visual area of cats, area 17, is located on the fold of the cortex called the lateral gyrus. These facts raise the question of how to reconcile the tangential arrangement of the orientation columns with the curvature of the gyrus. In the present study, we show a possible configuration of feature representation in the visual cortex using a three-dimensional (3D) self-organization model. We took into account preferred orientation, preferred direction, ocular dominance and retinotopy, assuming isotropic interaction. We performed computer simulation only in the middle layer at the beginning and expanded the range of simulation gradually to other layers, which was found to be a unique method in the present model for obtaining orientation columns spanning all the layers in the flat cortex. Vertical columns of preferred orientations were found in the flat parts of the model cortex. On the other hand, in the curved parts, preferred orientations were represented in wedge-like columns rather than straight columns, and preferred directions were frequently reversed in the deeper layers. Singularities associated with orientation representation appeared as warped lines in the 3D model cortex. Direction reversal appeared on the sheets that were delimited by orientation-singularity lines. These structures emerged from the balance between periodic arrangements of preferred orientations and vertical alignment of the same orientations. Our theoretical predictions about orientation representation were confirmed by multi-slice, high-resolution functional MRI in the cat visual cortex. We obtained a close agreement between theoretical predictions and experimental observations. The present study throws a doubt about the conventional columnar view of orientation representation, although more experimental data are needed.

Dataset Information

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

Background

Methodology/principal findings

Conclusions/significance

Publications

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

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