Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson's disease and incidental Parkinson's disease

Abstract

Lipid rafts are cholesterol- and sphingomyelin-enriched microdomains that provide a highly saturated and viscous physicochemical microenvironment to promote protein-lipid and protein-protein interactions. We purified lipid rafts from human frontal cortex from normal, early motor stages of Parkinson's disease (PD) and incidental Parkinson's disease (iPD) subjects and analyzed their lipid composition. We observed that lipid rafts from PD and iPD cortices exhibit dramatic reductions in their contents of n-3 and n-6 long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (22:6-n3) and arachidonic acid (20:4n-6). Also, saturated fatty acids (16:0 and 18:0) were significantly higher than in control brains. Paralleling these findings, unsaturation and peroxidability indices were considerably reduced in PD and iPD lipid rafts. Lipid classes were also affected in PD and iPD lipid rafts. Thus, phosphatidylserine and phosphatidylinositol were increased in PD and iPD, whereas cerebrosides and sulfatides and plasmalogen levels were considerably diminished. Our data pinpoint a dramatic increase in lipid raft order due to the aberrant biochemical structure in PD and iPD and indicate that these abnormalities of lipid rafts in the frontal cortex occur at early stages of PD pathology. The findings correlate with abnormal lipid raft signaling and cognitive decline observed during the development of these neurodegenerative disorders.

Figure 1

Western blot analyses of protein markers in fractions 1–6 from NSL, PD and PDi brain cortices. Equal amounts of total protein were used for NSL, PD and iPD samples. Standard molecular weight values are indicated (left).

Figure 2

Linear relationships for a subset of lipid parameters in lipid rafts from NSL, PD and iPD frontal cortices. Correlation coefficients and statistical significance are indicated in the text. Units are expressed as mole percentage for all variables.

Figure 3

Discriminant function analyses of groups NSL, PD and iPD. In the scatterplot, centroids are represented (□). Table in the right panel shows the variable matrix structure for each canonical function. For details and interpretation, see Results and Discussion.

Figure 4

(A) Comparative analyses of main lipid classes and fatty acid contents and relevant indices between control and PD frontal cortex gray matter. Results are expressed as percent of change versus NSL group. Eight cases were analyzed in each group. *P < 0.1 and P < 0.05, respectively. (B) Analyses of the lipid raft-to-cortex ratios for representative lipid classes and fatty acid contents as well as for representative indices in the NSL and PD groups. Cortical and lipid raft were processed individually for each case. *P < 0.05, ** P < 0.01 and ***P < 0.005 compared with NSL group.