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

Ichiro Kawahata,Luc Bousset,Kohji Fukunaga,Ronald Melki

doi:10.3390/ijms20215358

Abstract

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.

Highlights

Parkinson s disease (PD) [1] is a common neurodegenerative movement disorder which affects approximately 1% of people aged > 60 years [2,3]
In this study, using PD model dopaminergic neurons [30], we demonstrated that fatty acid-binding protein 3 (FABP3) is critical for α-Synuclein uptake and that knocking out FABP3 completely abolished the fibrillization of α-Synuclein
To investigate whether FABP3 is required for α-Synuclein uptake, we prepared cultured mesencephalic neurons derived from wild type or FABP3−/− C57BL6 mice and exposed them to 1 μM ATTO-550-labeled α-Synuclein monomer for 48 h

Summary

Introduction

Parkinson s disease (PD) [1] is a common neurodegenerative movement disorder which affects approximately 1% of people aged > 60 years [2,3]. Neuropathological features of PD include neuronal cell loss in the midbrain substantia nigra and the presence of cytoplasmic protein aggregates known as Lewy bodies (LBs) and Lewy neurites [4]. Α-Synuclein, a 140-amino acid protein associated with synaptic vesicles in presynaptic terminals [7], is the major filamentous component of LBs and Lewy neurites in PD and dementia with Lewy bodies (DLB) [8,9]. We recently demonstrated a relationship between the uptake of α-Synuclein assemblies and the appearance of pathological hallmarks of synucleinopathies [10,11,12]. The aggregation of α-Synuclein monomers is believed to play a crucial role in PD pathology. Α-Synuclein uptake by dopaminergic neurons is indispensable and may play a role in synucleinopathies [18,19]

Methods

Results

Conclusion