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

Ronald Melki¹  Luc Bousset¹  Ichiro Kawahata²  Kohji Fukunaga² 

[1] CEA, Institut François Jacob (MIRcen) and CNRS, Laboratory of Neurodegenerative Diseases, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France;Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan;

关键词: fatty acid-binding protein 3;    α-synuclein;    1-methyl-4-phenylpyridinium (mpp⁺);    mitochondria;    synucleinopathy;    parkinson’s disease;   

DOI  :  10.3390/ijms20215358

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown