Alpha-synuclein gene deletion decreases brain palmitate uptake and alters the palmitate metabolism in the absence of alpha-synuclein palmitate binding.
Alpha-synuclein is an abundant protein in the central nervous system that is associated with a number of neurodegenerative disorders, including Parkinson's disease. Its physiological function is poorly understood, although recently it was proposed to function as a fatty acid binding protein. To better define a role for alpha-synuclein in brain fatty acid uptake and metabolism, we infused awake, wild-type, or alpha-synuclein gene-ablated mice with [1-(14)C]palmitic acid (16:0) and assessed fatty acid uptake and turnover kinetics in brain phospholipids. Alpha-synuclein deficiency decreased brain 16:0 uptake 35% and reduced its targeting to the organic fraction. The incorporation coefficient for 16:0 entering the brain acyl-CoA pool was significantly decreased 36% in alpha-synuclein gene-ablated mice. Because incorporation coefficients alone are not predictive of fatty acid turnover in individual phospholipid classes, we calculated kinetic values for 16:0 entering brain phospholipid pools. Alpha-synuclein deficiency decreased the incorporation rate and fractional turnover of 16:0 in a number of phospholipid classes, but also increased the incorporation rate and fractional turnover of 16:0 in the choline glycerophospholipids. No differences in incorporation rate or turnover were observed in liver phospholipids, confirming that these changes in lipid metabolism were brain specific. Using titration microcalorimetry, we observed no binding of 16:0 or oleic acid to alpha-synuclein in vitro. Thus, alpha-synuclein has effects on 16:0 uptake and metabolism similar to those of an FABP, but unlike FABP, it does not directly bind 16:0; hence, the mechanism underlying these effects is different from that of a classical FABP.
Golovko
Mikhail Y
MY
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, Grand Forks, North Dakota 58202-9037, USA.
Faergeman
Nils J
NJ
Cole
Nelson B
NB
Castagnet
Paula I
PI
Nussbaum
Robert L
RL
Murphy
Eric J
EJ
D000214:Acyl Coenzyme A / Q000493:pharmacokinetics; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D007262:Infusions, Intravenous; D007700:Kinetics; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D019301:Oleic Acid / Q000493:pharmacokinetics; D019308:Palmitic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D010743:Phospholipids / Q000493:pharmacokinetics; D011485:Protein Binding / Q000235:genetics; D051843:Synucleins; D051844:alpha-Synuclein
D000214:Acyl Coenzyme A; D002250:Carbon Radioisotopes; D009419:Nerve Tissue Proteins; D010743:Phospholipids; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D019301:Oleic Acid; D019308:Palmitic Acid