Abstract
Calcium-independent phospholipase A2 group VIa (iPLA2β) preferentially releases docosahexaenoic acid (DHA) from the sn-2 position of phospholipids. Mutations of its gene, PLA2G6, are found in patients with several progressive motor disorders, including Parkinson disease. At 4 months, PLA2G6 knockout mice (iPLA2β−/−) show minimal neuropathology but altered brain DHA metabolism. By 1 year, they develop motor disturbances, cerebellar neuronal loss, and striatal α-synuclein accumulation. We hypothesized that older iPLA2β−/− mice also would exhibit inflammatory and other neuropathological changes. Real-time polymerase chain reaction and Western blotting were performed on whole brain homogenate from 15 to 20-month old male iPLA2β−/− or wild-type (WT) mice. These older iPLA2β−/− mice compared with WT showed molecular evidence of microglial (CD-11b, iNOS) and astrocytic (glial fibrillary acidic protein) activation, disturbed expression of enzymes involved in arachidonic acid metabolism, loss of neuroprotective brain derived neurotrophic factor, and accumulation of cytokine TNF-α messenger ribonucleic acid, consistent with neuroinflammatory pathology. There was no evidence of synaptic loss, of reduced expression of dopamine active reuptake transporter, or of accumulation of the Parkinson disease markers Parkin or Pink1. iPLA2γ expression was unchanged. iPLA2β deficient mice show evidence of neuroinflammation and associated neuropathology with motor dysfunction in later life. These pathological biomarkers could be used to assess efficacy of dietary intervention, antioxidants or other therapies on disease progression in this mouse model of progressive human motor diseases associated with a PLA2G6 mutation.
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Acknowledgments
The authors thank the NIH Fellow Editorial Board and Ms. Mairi Stevens for editorial assistance and Dr. Dede Greenstein for statistical support. Research was supported by the Intramural Research Program of the National Institute on Aging and, for JT, by United States Public Health Service Grants R37-DK34388, P41-RR00954, P60-DK20579, and P30-DK56341.
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Blanchard, H., Taha, A.Y., Cheon, Y. et al. iPLA2β Knockout Mouse, a Genetic Model for Progressive Human Motor Disorders, Develops Age-Related Neuropathology. Neurochem Res 39, 1522–1532 (2014). https://doi.org/10.1007/s11064-014-1342-y
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DOI: https://doi.org/10.1007/s11064-014-1342-y