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

Ichiro Kawahata (1) , Luc Bousset (2) , Ronald Melki (2) , Kohji Fukunaga (1)

1 Tohoku University [Sendai]
2 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199

α-Synuclein is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson s disease and other synucleinopathies. Fatty acids partially regulate α-Synuclein accumulation, and mesencephalic dopaminergic neurons highly express fatty acid-binding protein 3 (FABP3). We previously demonstrated that FABP3 knockout mice show decreased α-Synuclein oligomerization and neuronal degeneration of tyrosine hydroxylase (TH)-positive neurons in vivo. In this study, we newly investigated the importance of FABP3 in α-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 α-Synuclein monomers while FABP3 −/− TH + neurons do not. The formation of filamentous α-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 α-Synuclein uptake in dopaminergic neurons, thereby preventing synucleinopathies, including Parkinson s disease.

Mots clés: fatty acid-binding protein 3; α-Synuclein; 1-methyl-4-phenylpyridinium (MPP + ); mitochondria; synucleinopathy; Parkinson's disease

Domaines: Sciences du Vivant [q-bio]; Biochimie, Biologie Moléculaire; Neurosciences [q-bio.NC]; Biologie cellulaire

Ichiro Kawahata, Luc Bousset, Ronald Melki, Kohji Fukunaga. Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP+-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons. International Journal of Molecular Sciences, 2019, 20 (21), pp.5358. ⟨10.3390/ijms20215358⟩. ⟨cea-02347477⟩