Development of FABP3 ligands that inhibit arachidonic acid-induced α-synuclein oligomerization

Cheng, An; Shinoda, Yasuharu; Yamamoto, Tetsunori; Miyachi, Hiroyuki; Fukunaga, Kohji

doi:10.1016/j.brainres.2018.11.036

Cited by 50Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNuclear Receptors and Signaling

Development of FABP3 ligands that inhibit arachidonic acid-induced α-synuclein oligomerization

Cheng, An, Shinoda, Yasuharu, Yamamoto, Tetsunori, Miyachi, Hiroyuki, Fukunaga, Kohji·2019·Brain Research

DOI 10.1016/j.brainres.2018.11.036

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Abstract

In Parkinson's disease (PD), α-synuclein (αSyn) accumulation and inclusion triggers dopamine neuronal death and synapse dysfunction in vivo. We previously reported that fatty acid-binding protein 3 (FABP3) is highly expressed in the brain and accelerates αSyn oligomerization when cells are exposed to 1-Methyl-1,2,3,6-tetrahydropiridine (MPTP). Here, we demonstrate that αSyn oligomerization was markedly enhanced by co-overexpressing FABP3 in neuro-2A cells when cells were treated with arachidonic acid (AA). We developed FABP3 ligands, which bind to the fatty acid binding domain of FABP3, using an 8-Anilinonaphthalene-1-sulfonic acid (ANS) assay with a recombinant FABP3 protein. The prototype for the FABP4 ligand, BMS309403, has no affinity for FABP3. We developed more FABP3-specific ligands derived from the chemical structure of BMS309403. Like AA, ligands 1, 7, and 8 had a relatively high affinity for FAPB3 in the ANS assay. Then, we evaluated the inhibition of αSyn oligomerization in neuro-2A cells co-overexpressing FABP3 and αSyn. Importantly, AA treatments markedly enhanced αSyn oligomerization in the co-expressing cells. Ligands 1, 7, and 8 significantly reduced AA-induced αSyn oligomerization in neuro-2A cells. Taken together, our results indicate that FABP3 ligands that target FABP3 may be used as potential therapeutics that inhibit αSyn aggregation in vivo.

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FABP3 ligand inhibits α-synuclein oligomerization in PD mouse models.
“Intriguingly, FABP3 ligand, which we have recently synthesized, inhibits α-synuclein oligomerization in PD mouse models [150,151].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [151]

α-Synuclein in Lewy bodies
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382 · see citing works
AGEING AND PARKINSON'S DISEASE: SUBSTANTIA NIGRA REGIONAL SELECTIVITY
FEARNLEY, J. M., & LEES, A. J. (1991) · Brain · doi:10.1093/brain/114.5.2283 · Cited by 3,529 · see citing works
Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic Membranes
Davidson, W. S., Jonas, A., Clayton, D. F., & George, J. M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.16.9443 · Cited by 1,588 · see citing works
In vivo demonstration that α-synuclein oligomers are toxic
Winner, B., Jappelli, R., Maji, S. K., Desplats, P., Boyer, L. F., Aigner, S., Hetzer, C., Loher, T., Vilar, M., Campioni, S., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100976108 · Cited by 1,487 · see citing works
Alpha-synuclein and neurodegenerative diseases
Goedert, M. (2001) · Nature reviews. Neuroscience · doi:10.1038/35081564 · Cited by 1,402 · see citing works
Basal Lipid Peroxidation in Substantia Nigra Is Increased in Parkinson's Disease
Dexter, D. T., Carter, C. J., Wells, F. R., Javoy-Agid, F., Agid, Y., Lees, A. J., Jenner, P. G., & MARSDEN, C. D. (1989) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1989.tb09133.x · Cited by 1,397 · see citing works
Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains
Riederer, P., Sofic, E., Rausch, W., Schmidt, B., Reynolds, G. P., Jellinger, K., & Youdim, M. B. H. (1989) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1989.tb09150.x · Cited by 1,383 · see citing works
Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein
Cremades, N., Cohen, S. I. A., Deas, E., Abramov, A. Y., Chen, A. Y., Orte, Á., Sandal, M., Clarke, R. W., Dunne, P., Aprile, F. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.037 · Cited by 901 · see citing works
Role of mitochondrial <scp>ROS</scp> in the brain: from physiology to neurodegeneration
Angelova, P. R., & Abramov, A. Y. (2018) · FEBS Letters · doi:10.1002/1873-3468.12964 · Cited by 789 · see citing works
Vesicle Permeabilization by Protofibrillar α-Synuclein: Implications for the Pathogenesis and Treatment of Parkinson's Disease
Volles, M. J., Lee, S., Rochet, J., Shtilerman, M. D., Ding, T. T., Kessler, J. C., & Lansbury, P. T. (2001) · Biochemistry · doi:10.1021/bi0102398 · Cited by 682 · see citing works
Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease
Sofic, E., Lange, K. W., Jellinger, K. A., & Riederer, P. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90355-b · Cited by 591 · see citing works
The Formation of Highly Soluble Oligomers of α-Synuclein Is Regulated by Fatty Acids and Enhanced in Parkinson's Disease
Sharon, R., Bar-Joseph, I., Frosch, M. P., Walsh, D. M., Hamilton, J. A., & Selkoe, D. J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00024-2 · Cited by 562 · see citing works
Membrane-bound α-Synuclein Has a High Aggregation Propensity and the Ability to Seed the Aggregation of the Cytosolic Form
Lee, H.-J., Choi, C., & Lee, S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m107045200 · Cited by 452 · see citing works
The Association of α-Synuclein with Membranes Affects Bilayer Structure, Stability, and Fibril Formation
Zhu, M., Li, J., & Fink, A. L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305326200 · Cited by 325 · see citing works
Insights into binding of fatty acids by fatty acid binding proteins
Hanhoff, T., Lücke, C., & Spener, F. (2002) · Molecular and Cellular Biochemistry · doi:10.1023/a:1020502624234 · Cited by 209 · see citing works
Cerebrospinal Fluid Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Combination with Subcortical and Cortical Biomarkers in Vascular Dementia and Alzheimer's Disease
Bjerke, M., Zetterberg, H., Edman, Å., Blennow, K., Wallin, A., & Andreasson, U. (2011) · Journal of Alzheimer's Disease · doi:10.3233/jad-2011-110566 · Cited by 180 · see citing works
Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP)
Sulsky, R. B., Magnin, D. R., Huang, Y., Simpkins, L. M., Taunk, P. C., Patel, M. M., Zhu, Y., Stouch, T. R., Bassolino‐Klimas, D., Parker, R. A., et al. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.12.044 · Cited by 149 · see citing works
Differential role of CSF fatty acid binding protein 3, α-synuclein, and Alzheimer’s disease core biomarkers in Lewy body disorders and Alzheimer’s dementia
Chiasserini, D., Biscetti, L., Eusebi, P., Salvadori, N., Frattini, G., Simoni, S., Roeck, N. D., Tambasco, N., Stoops, E., Vanderstichele, H., et al. (2017) · Alzheimer s Research & Therapy · doi:10.1186/s13195-017-0276-4 · Cited by 138 · see citing works
Postmortem brain fatty acid profile of levodopa-treated Parkinson disease patients and parkinsonian monkeys
Julien, C., Berthiaume, L., Tahar, A. H., Rajput, A. H., Bédard, P. J., Paolo, T. D., Julien, P., & Calon, F. (2006) · Neurochemistry International · doi:10.1016/j.neuint.2005.12.002 · Cited by 114 · see citing works
α‐Synuclein oligomers oppose long‐term potentiation and impair memory through a calcineurin‐dependent mechanism: relevance to human synucleopathic diseases
Martin, Z. S., Neugebauer, V., Dineley, K. T., Kayed, R., Zhang, W., Reese, L. C., & Taglialatela, G. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07576.x · Cited by 113 · see citing works
Heart-Type Fatty Acid Binding Protein Regulates Dopamine D2Receptor Function in Mouse Brain
Shioda, N., Yamamoto, Y., Watanabe, M., Binas, B., Owada, Y., & Fukunaga, K. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4140-09.2010 · Cited by 101 · see citing works
Self-citation
FABP3 Protein Promotes α-Synuclein Oligomerization Associated with 1-Methyl-1,2,3,6-tetrahydropiridine-induced Neurotoxicity
Shioda, N., Yabuki, Y., Kobayashi, Y., Onozato, M., Owada, Y., & Fukunaga, K. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.527341 · Cited by 95 · see citing works
Self-citation
Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD
Esteves, A. R., Arduíno, D. M., Silva, D. F., Oliveira, C. R., & Cardoso, S. M. (2011) · Parkinson s Disease · doi:10.4061/2011/693761 · Cited by 89 · see citing works
Phosphorylated Tau-Aβ42 Ratio as a Continuous Trait for Biomarker Discovery for Early-Stage Alzheimer’s Disease in Multiplex Immunoassay Panels of Cerebrospinal Fluid
Harari, O., Cruchaga, C., Kauwe, J. S. K., Ainscough, B. J., Bales, K., Pickering, E. H., Bertelsen, S., Fagan, A. M., Holtzman, D. M., Morris, J. C., et al. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.11.032 · Cited by 82 · see citing works
Serum Heart-Type Fatty Acid-Binding Protein and Cerebrospinal Fluid Tau: Marker Candidates for Dementia with Lewy Bodies
Mollenhauer, B., Steinacker, P., Bahn, E., Bibl, M., Brechlin, P., Schlossmacher, M. G., Locascio, J. J., Wiltfang, J., Kretzschmar, H. A., Poser, S., et al. (2007) · Neurodegenerative Diseases · doi:10.1159/000105157 · Cited by 81 · see citing works
A potential cerebrospinal fluid and plasmatic marker for the diagnosis of Creutzfeldt‐Jakob disease
Guillaume, E., Zimmermann, C., Burkhard, P. R., Hochstrasser, D. F., & Sanchez, J. (2003) · PROTEOMICS · doi:10.1002/pmic.200300478 · Cited by 80 · see citing works
Expression of E‐FABP in PC12 cells increases neurite extension during differentiation: involvement of n‐3 and n‐6 fatty acids
Liu, J., Almaguel, F. G., Bu, L., León, D. D., & León, M. A. D. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05507.x · Cited by 71 · see citing works
Impact of the carotenoid astaxanthin on phagocytic capacity and ROS/RNS production of human neutrophils treated with free fatty acids and high glucose
Guerra, B. A., & Otton, R. (2011) · International Immunopharmacology · doi:10.1016/j.intimp.2011.10.004 · Cited by 69 · see citing works
Raised calcium and oxidative stress cooperatively promote alpha-synuclein aggregate formation
Goodwin, J., Nath, S., Engelborghs, Y., & Pountney, D. L. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.11.004 · Cited by 65 · see citing works
Protection of dopaminergic neurons by 5-lipoxygenase inhibitor
Kang, K., Liou, H.-H., Hour, M., et al. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.06.014 · Cited by 61 · see citing works
Overexpression of FABP3 promotes apoptosis through inducing mitochondrial impairment in embryonic cancer cells
Song, G., Shen, Y.-H., Liu, Y.-Q., Sun, W., Miao, L., Zhou, L., Liu, H.-L., Yang, R., Kong, X.-Q., Cao, K., et al. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24243 · Cited by 58 · see citing works
Polyunsaturated fatty acids induce ovarian cancer cell death through ROS-dependent MAP kinase activation
Tanaka, A., Yamamoto, A., Murota, K., et al. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.08.168 · Cited by 50 · see citing works
Sequential Extraction of Soluble and Insoluble Alpha-Synuclein from Parkinsonian Brains
Bandopadhyay, R. (2016) · Journal of Visualized Experiments · doi:10.3791/53415 · Cited by 48 · see citing works
Ubiquitin proteasome system in Parkinson's disease: A keeper or a witness?
Martins-Branco, D. A., Esteves, A. R., Santos, D., Arduíno, D. M., Swerdlow, R. H., Oliveira, C. R., Januário, C., & Cardoso, S. M. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.08.008 · Cited by 44 · see citing works
Serum heart-fatty acid binding protein levels in patients with Lewy body disease
Wada‐Isoe, K., Imamura, K., Michio, K., Kowa, H., & Nakashima, K. (2007) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2007.08.018 · Cited by 42 · see citing works
Arachidonic acid causes hidden blood loss–like red blood cell damage through oxidative stress reactions
Yuan, T., Cong, Y., Meng, J., Qian, H., Ye, W., Sun, W., Zhao, J.-N., & Bao, N.-R. (2016) · Journal of Surgical Research · doi:10.1016/j.jss.2016.11.060 · Cited by 41 · see citing works
Motor impairment and aberrant production of neurochemicals in human α-synuclein A30P+A53T transgenic mice with α-synuclein pathology
Ikeda, M., Kawarabayashi, T., Harigaya, Y., Sasaki, A., Yamada, S., Matsubara, E., Murakami, T., Tanaka, Y., Kurata, T., Wuhua, X., et al. (2008) · Brain Research · doi:10.1016/j.brainres.2008.10.011 · Cited by 32 · see citing works
Structure-guided design, synthesis and in vitro evaluation of a series of pyrazole-based fatty acid binding protein (FABP) 3 ligands
Beniyama, Y., Matsuno, K., & Miyachi, H. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.01.054 · Cited by 31 · see citing works
Self-citation
Cerebrospinal Fluid Fatty Acid-Binding Protein 3 is Related to Dementia Development in a Population-Based Sample of Older Adult Women Followed for 8 Years
Bjerke, M., Kern, S., Blennow, K., Zetterberg, H., Wærn, M., Börjesson‐Hanson, A., Östling, S., Kern, J., & Skoog, I. G. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150525 · Cited by 22 · see citing works
Dopamine prevents lipid peroxidation-induced accumulation of toxic α-synuclein oligomers by preserving autophagy-lysosomal function
Jiang, P., Gan, M., & Yen, S.-H. C. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00081 · Cited by 17 · see citing works
Fatty acid-binding protein3 expression in BeWo cells, a human placental choriocarcinoma cell line
Leroy, C., Tobin, K. A. R., Basak, S., et al. (2017) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2017.04.002 · Cited by 12 · see citing works
Discovery of disease-modifying drug inhibiting alpha-synuclein aggregation in Parkinson's disease model mice
Fukunaga, K., Yabuki, Y., Matsuo, K., Izumi, H., & Shinoda, Y. (2018) · Proceedings for Annual Meeting of The Japanese Pharmacological Society · doi:10.1254/jpssuppl.wcp2018.0_or5-4 · Cited by 1 · see citing works
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Dumancas, G. G., Murdianti, B. S., & Lucas, E. A. (2013) · Medical Entomology and Zoology · Cited by 2 · see citing works
UVB irradiation induces changes in the distribution and release of 14C-arachidonic acid in human keratinocytes in culture
Punnonen, K. R. A., Puustinen, T., & Jansén, C. T. (1986) · Archives of Dermatological Research · doi:10.1007/bf00455160 · Cited by 9 · see citing works
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Chilton, F. H., Hadley, J. S., & Murphy, R. C. (1987) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(87)90282-7 · Cited by 51 · see citing works
Proliferation-dependent changes in release of arachidonic acid from endothelial cells.
Whatley, R. E., Satoh, K., Zimmerman, G. A., et al. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117539 · Cited by 42 · see citing works
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Authors: Cheng, A., Shinoda, Y., Yamamoto, T., Miyachi, H., & Fukunaga, K.
Affiliations: Tohoku University (JP)
The University of Tokyo (JP)
Corresponding author: Fukunaga, Kohji
ORCID: Cheng, An
Shinoda, Yasuharu
Miyachi, Hiroyuki
Fukunaga, Kohji
Venue: Brain Research
Publisher: Elsevier BV
Published: 2019-03
Volume: 1707
Pages: 190-197
ISSN: 0006-8993 (ISSN-L)
DOI: 10.1016/j.brainres.2018.11.036
OpenAlex: W2902172038
Cited by: 50
References: 42
Citations by year: 2026: 3 · 2025: 6 · 2024: 4 · 2023: 9 · 2022: 2 · 2021: 14 · 2020: 7 · 2019: 5
FWCI: 4.41
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Brain Research (publishedVersion)
PubMed (publishedVersion)
Funders: Japan Society for the Promotion of Science (16H05219)
Topics: Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords: FABP3, alpha-synuclein oligomerization, arachidonic acid, Parkinson's disease, BMS309403, N2a cells, alpha-synuclein aggregation, neuroprotection
MeSH terms: Fatty Acid Binding Protein 3, Synucleinopathies, Animals, Brain, Dopamine, Ligands, Parkinson Disease, Substantia Nigra, Arachidonic Acid, Cell Line, Tumor, Mice, alpha-Synuclein, Dopaminergic Neurons

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Development of FABP3 ligands that inhibit arachidonic acid-induced α-synuclein oligomerization

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