FABP3 protein promotes α-synuclein oligomerization associated with 1-methyl-1,2,3,6-tetrahydropiridine-induced neurotoxicity.

α-Synuclein (αSyn) accumulation in dopaminergic (DA) neurons is partly regulated by long-chain polyunsaturated fatty acids. We found that fatty acid-binding protein 3 (FABP3, H-FABP), a factor critical for arachidonic acid (AA) transport and metabolism in brain, is highly expressed in DA neurons. Fabp3 knock-out (Fabp3(-/-)) mice were resistant to 1-methyl-1,2,3,6-tetrahydropiridine-induced DA neurodegeneration in the substantia nigra pars compacta and showed improved motor function. Interestingly, FABP3 interacted with αSyn in the substantia nigra pars compacta, and αSyn accumulation following 1-methyl-1,2,3,6-tetrahydropiridine treatment was attenuated in Fabp3(-/-) compared with wild-type mice. We confirmed that FABP3 overexpression aggravates AA-induced αSyn oligomerization and promotes cell death in PC12 cells, whereas overexpression of a mutant form of FABP3 lacking fatty-acid binding capacity did not. Taken together, αSyn oligomerization in DA neurons is likely aggravated by AA through FABP3 in Parkinson disease pathology.