Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP<sup>+</sup>-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons
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 prote...
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2019-10-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/20/21/5358 |
id |
doaj-d7dbdd6dd2cf4127a9e7614961ecf3a8 |
---|---|
record_format |
Article |
spelling |
doaj-d7dbdd6dd2cf4127a9e7614961ecf3a82020-11-24T21:11:03ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-10-012021535810.3390/ijms20215358ijms20215358Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP<sup>+</sup>-Induced Mitochondrial Dysfunction in Cultured Dopaminergic NeuronsIchiro Kawahata0Luc Bousset1Ronald Melki2Kohji Fukunaga3Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanCEA, Institut François Jacob (MIRcen) and CNRS, Laboratory of Neurodegenerative Diseases, 18 Route du Panorama, 92265 Fontenay-aux-Roses, FranceCEA, Institut François Jacob (MIRcen) and CNRS, Laboratory of Neurodegenerative Diseases, 18 Route du Panorama, 92265 Fontenay-aux-Roses, FranceDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japanα-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 <i>in vivo</i>. In this study, we newly investigated the importance of FABP3 in α-Synuclein uptake, 1-methyl-4-phenylpyridinium (MPP<sup>+</sup>)-induced axodendritic retraction, and mitochondrial dysfunction. To disclose the issues, we employed cultured mesencephalic neurons derived from wild type or FABP3<sup>−/−</sup> C57BL6 mice and performed immunocytochemical analysis. We demonstrated that TH<sup>+</sup> neurons from FABP3<sup>+/+</sup> mice take up α-Synuclein monomers while FABP3<sup>−/−</sup> TH<sup>+</sup> neurons do not. The formation of filamentous α-Synuclein inclusions following treatment with MPP<sup>+</sup> was observed only in FABP3<sup>+/+</sup>, and not in FABP3<sup>−/−</sup> neurons. Notably, detailed morphological analysis revealed that FABP<sup>−/−</sup> neurons did not exhibit MPP<sup>+</sup>-induced axodendritic retraction. Moreover, FABP3 was also critical for MPP<sup>+</sup>-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.https://www.mdpi.com/1422-0067/20/21/5358fatty acid-binding protein 3α-synuclein1-methyl-4-phenylpyridinium (mpp<sup>+</sup>)mitochondriasynucleinopathyparkinson’s disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ichiro Kawahata Luc Bousset Ronald Melki Kohji Fukunaga |
spellingShingle |
Ichiro Kawahata Luc Bousset Ronald Melki Kohji Fukunaga Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP<sup>+</sup>-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons International Journal of Molecular Sciences fatty acid-binding protein 3 α-synuclein 1-methyl-4-phenylpyridinium (mpp<sup>+</sup>) mitochondria synucleinopathy parkinson’s disease |
author_facet |
Ichiro Kawahata Luc Bousset Ronald Melki Kohji Fukunaga |
author_sort |
Ichiro Kawahata |
title |
Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP<sup>+</sup>-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons |
title_short |
Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP<sup>+</sup>-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons |
title_full |
Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP<sup>+</sup>-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons |
title_fullStr |
Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP<sup>+</sup>-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons |
title_full_unstemmed |
Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP<sup>+</sup>-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons |
title_sort |
fatty acid-binding protein 3 is critical for α-synuclein uptake and mpp<sup>+</sup>-induced mitochondrial dysfunction in cultured dopaminergic neurons |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-10-01 |
description |
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 <i>in vivo</i>. In this study, we newly investigated the importance of FABP3 in α-Synuclein uptake, 1-methyl-4-phenylpyridinium (MPP<sup>+</sup>)-induced axodendritic retraction, and mitochondrial dysfunction. To disclose the issues, we employed cultured mesencephalic neurons derived from wild type or FABP3<sup>−/−</sup> C57BL6 mice and performed immunocytochemical analysis. We demonstrated that TH<sup>+</sup> neurons from FABP3<sup>+/+</sup> mice take up α-Synuclein monomers while FABP3<sup>−/−</sup> TH<sup>+</sup> neurons do not. The formation of filamentous α-Synuclein inclusions following treatment with MPP<sup>+</sup> was observed only in FABP3<sup>+/+</sup>, and not in FABP3<sup>−/−</sup> neurons. Notably, detailed morphological analysis revealed that FABP<sup>−/−</sup> neurons did not exhibit MPP<sup>+</sup>-induced axodendritic retraction. Moreover, FABP3 was also critical for MPP<sup>+</sup>-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. |
topic |
fatty acid-binding protein 3 α-synuclein 1-methyl-4-phenylpyridinium (mpp<sup>+</sup>) mitochondria synucleinopathy parkinson’s disease |
url |
https://www.mdpi.com/1422-0067/20/21/5358 |
work_keys_str_mv |
AT ichirokawahata fattyacidbindingprotein3iscriticalforasynucleinuptakeandmppsupsupinducedmitochondrialdysfunctionincultureddopaminergicneurons AT lucbousset fattyacidbindingprotein3iscriticalforasynucleinuptakeandmppsupsupinducedmitochondrialdysfunctionincultureddopaminergicneurons AT ronaldmelki fattyacidbindingprotein3iscriticalforasynucleinuptakeandmppsupsupinducedmitochondrialdysfunctionincultureddopaminergicneurons AT kohjifukunaga fattyacidbindingprotein3iscriticalforasynucleinuptakeandmppsupsupinducedmitochondrialdysfunctionincultureddopaminergicneurons |
_version_ |
1716754735944433664 |