title: Alpha-synuclein gene ablation increases docosahexaenoic acid incorporation and turnover in brain phospholipids.
abstract: Previously, we demonstrated that ablation of alpha-synuclein (Snca) reduces arachidonate (20:4n-6) turnover in brain phospholipids through modulation of an endoplasmic reticulum-localized acyl-CoA synthetase (Acsl). The effect of Snca ablation on docosahexaenoic acid (22:6n-3) metabolism is unknown. In the present study, we examined the effect of Snca gene ablation on brain 22:6n-3 metabolism. We determined 22:6n-3 uptake and incorporation into brain phospholipids by infusing awake, wild-type and Snca-/- mice with [1-14C]22:6n-3 using steady-state kinetic modeling. In addition, because Snca modulates 20:4n-6-CoA formation, we assessed microsomal Acsl activity using 22:6n-3 as a substrate. Although Snca gene ablation does not affect brain 22:6n-3 uptake, brain 22:6n-3-CoA mass was elevated 1.5-fold in the absence of Snca. This is consistent with the 1.6- to 2.2-fold increase in the incorporation rate and turnover in ethanolamine glycerophospholipid, phosphatidylserine, and phosphatidylinositol pools. Increased 22:6n-3-CoA mass was not the result of altered Acsl activity, which was unaffected by the absence of Snca. While Snca bound 22:6n-3, Kd = 1.0 +/- 0.5 micromol/L, it did not bind 22:6n-3-CoA. These effects of Snca gene deletion on 22:6n-3 brain metabolism are opposite to what we reported previously for brain 20:4n-6 metabolism and are likely compensatory for the decreased 20:4n-6 metabolism in brains of Snca-/- mice.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, Grand Forks, North Dakota 58202-9037, USA.
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Golovko
authors.forename: Thad A
authors.initials: TA
authors.lastname: Rosenberger
authors.forename: Søren
authors.initials: S
authors.lastname: Feddersen
authors.forename: Nils J
authors.initials: NJ
authors.lastname: Faergeman
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D002250:Carbon Radioisotopes; D003066:Coenzyme A Ligases / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D007700:Kinetics; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D002250:Carbon Radioisotopes; D010743:Phospholipids; D051844:alpha-Synuclein; D004281:Docosahexaenoic Acids; D003066:Coenzyme A Ligases; C561832:Acsl1 protein, rat