Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA(2)β (VIA)-deficient mice.
Ca(2+)-independent phospholipase A(2)β (iPLA(2)β) selectively hydrolyzes docosahexaenoic acid (DHA, 22:6n-3) in vitro from phospholipid. Mutations in the PLA2G6 gene encoding this enzyme occur in patients with idiopathic neurodegeneration plus brain iron accumulation and dystonia-parkinsonism without iron accumulation, whereas mice lacking PLA2G6 show neurological dysfunction and neuropathology after 13 months. We hypothesized that brain DHA metabolism and signaling would be reduced in 4-month-old iPLA(2)β-deficient mice without overt neuropathology. Saline or the cholinergic muscarinic M(1,3,5) receptor agonist arecoline (30 mg/kg) was administered to unanesthetized iPLA(2)β(-/-), iPLA(2)β(+/-), and iPLA(2)β(+/+) mice, and [1-(14)C]DHA was infused intravenously. DHA incorporation coefficients k* and rates J(in), representing DHA metabolism, were determined using quantitative autoradiography in 81 brain regions. iPLA(2)β(-/-) or iPLA(2)β(+/-) compared with iPLA(2)β(+/+) mice showed widespread and significant baseline reductions in k* and J(in) for DHA. Arecoline increased both parameters in brain regions of iPLA(2)β(+/+) mice but quantitatively less so in iPLA(2)β(-/-) and iPLA(2)β(+/-) mice. Consistent with iPLA(2)β's reported ability to selectively hydrolyze DHA from phospholipid in vitro, iPLA(2)β deficiency reduces brain DHA metabolism and signaling in vivo at baseline and following M(1,3,5) receptor activation. Positron emission tomography might be used to image disturbed brain DHA metabolism in patients with PLA2G6 mutations.
Basselin
Mireille
M
Brain Physiology and Metabolism Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Rosa
Angelo O
AO
Ramadan
Epolia
E
Cheon
Yewon
Y
Chang
Lisa
L
Chen
Mei
M
Greenstein
Deanna
D
Wohltmann
Mary
M
Turk
John
J
Rapoport
Stanley I
SI
D000818:Animals; D001115:Arecoline / Q000008:administration & dosage / Q000494:pharmacology; D001835:Body Weight; D001921:Brain / Q000098:blood supply / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002536:Cerebral Arteries / Q000502:physiology; D004281:Docosahexaenoic Acids / Q000097:blood / Q000378:metabolism*; D054522:Group VI Phospholipases A2 / Q000172:deficiency* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D057054:Molecular Imaging; D015398:Signal Transduction
D004281:Docosahexaenoic Acids; D001115:Arecoline; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse