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.
Highlights
Parkinson’s disease (PD) is a multisystemic neurodegenerative disease that affects selected nuclei of the medulla oblongata and pons, olfactory bulb and tract, intestinal ganglionic plexus, substantia nigra pars compacta, amygdala, nucleus basalis of Meynert and cerebral cortex
The unsaturation index was reduced by 38% in PD and 52% in incidental PD (iPD) compared with controls, indicating that lipid rafts in PD and iPD are significantly more viscous and liquid-ordered structures than in controls
Similar reductions were observed in the levels of these two fatty acids in iPD lipid rafts (79% and 66% for docosahexaenoic acid (DHA) and arachidonic acid (AA), respectively)
Summary
Parkinson’s disease (PD) is a multisystemic neurodegenerative disease that affects selected nuclei of the medulla oblongata and pons, olfactory bulb and tract, intestinal ganglionic plexus, substantia nigra pars compacta, amygdala, nucleus basalis of Meynert and cerebral cortex. Cases with Lewy body pathology in the brain stem without motor symptoms are considered as having incidental PD (iPD) because they are unexpectedly discovered after appropriate postmortem neuropathological study [5,6,7,8]. Whether these cases constitute premotor PD has been a matter of controversy for some years, because it cannot be confirmed that these cases would have progressed to Parkinsonism if they had survived longer. The study of consecutive cases in a large series and the recognition of several intermediate degrees of involvement of the brain stem, limbic structures and, eventually, the cerebral cortex make it clear that a prediction of iPD as an anterior stage of PD seems more than reasonable [2,9,10,11]
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