Fatty Acid-Binding Protein 3 is Critical for ?-Synuclein Uptake and MPP+-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons.

ABSTRACT: ?-Synuclein is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson's disease and other synucleinopathies. Fatty acids partially regulate ?-Synuclein accumulation, and mesencephalic dopaminergic neurons highly express fatty acid-binding protein 3 (FABP3). We previously demonstrated that FABP3 knockout mice show decreased ?-Synuclein oligomerization and neuronal degeneration of tyrosine hydroxylase (TH)-positive neurons in vivo. In this study, we newly investigated the importance of FABP3 in ?-Synuclein uptake, 1-methyl-4-phenylpyridinium (MPP+)-induced axodendritic retraction, and mitochondrial dysfunction. To disclose the issues, we employed cultured mesencephalic neurons derived from wild type or FABP3-/- C57BL6 mice and performed immunocytochemical analysis. We demonstrated that TH+ neurons from FABP3+/+ mice take up ?-Synuclein monomers while FABP3-/- TH+ neurons do not. The formation of filamentous ?-Synuclein inclusions following treatment with MPP+ was observed only in FABP3+/+, and not in FABP3-/- neurons. Notably, detailed morphological analysis revealed that FABP-/- neurons did not exhibit MPP+-induced axodendritic retraction. Moreover, FABP3 was also critical for MPP+-induced reduction of mitochondrial activity and the production of reactive oxygen species. These data indicate that FABP3 is critical for ?-Synuclein uptake in dopaminergic neurons, thereby preventing synucleinopathies, including Parkinson's disease.

SUBMITTER: Kawahata I 

PROVIDER: S-EPMC6862506 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature