Search

An aging society leads to an increased number of patients with cognitive and movement disorders, such as Parkinson's disease and dementia with Lewy bodies. α-Synuclein accumulation in neuronal cells is a pathological hallmark of α-synucleinopathies. Aberrant soluble oligomeric units of α-synuclein are toxic and disrupt neuronal homeostasis. Fatty acids partially regulate α-synuclein accumulation as well as oligomerization, and fatty acid-binding protein (FABP) associates with the α-synuclein aggregates. Heart-type FABP (hFABP, FABP3) is rich in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D 2L ), which is abundant in caveolae. We recently demonstrated that mesencephalic neurons require FABP3 and dopamine D 2L receptors for the caveolae-mediated α-synuclein uptake. Accumulated α-synuclein gets fibrillized and tightly co-localizes with FABP3 and dopamine D 2L receptors, which leads to mitochondrial dysfunction and loss of tyrosine hydroxylase, a rate-limiting enzyme in dopamine production. Furthermore, the inhibition of FABP3 using small-molecule ligands successfully prevents FABP3-induced neurotoxicity. In this review, we focus on the impact of FABP3, dopamine receptors, and other FABP family proteins in the process of α-synuclein propagation and the subsequent aggregate-induced cytotoxicity. We also propose the potential of FABP as a therapeutic target for α-synucleinopathies., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Accumulation and aggregation of α-synuclein (αSyn) trigger neuronal loss in the substantia nigra pars compacta (SNpc), which in turn causes motor symptoms in Parkinson's disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3), an intracellular fatty acid carrier protein, enhances αSyn neurotoxicity in SNpc and motor impairments after intranigral injection of αSyn fibrils. However, the temporal profile of αSyn fibril spread and their toxicity remains unclear. In the present study, we investigated the temporal profile of αSyn fibril spread and its toxicity, which induces intracellular fibril formation. Monomeric and fibrillar aSyn assemblies were labeled with ATTO550 to distinguish the exogenous form from the endogenous species and injected into bilateral striatum in Fabp3 +/+ (wild type) and Fabp3 -/- mice. Accumulation of both monomeric and fibrillar exogenous αSyn in the SNpc was drastically decreased in Fabp3 -/- mice compared to that in the Fabp3 +/+ counterparts. Deletion of Fabp3 also prevented exogenous αSyn fibril-induced seeding of the endogenous αSyn into aggregates containing phosphorylated and filamentous forms in the SNpc. Consistent with these results, loss of dopaminergic neurons and subsequent impaired motor behavior were attenuated in Fabp3 -/- mice. These results highlight the crucial role of FABP3 in pathogenic αSyn accumulation and its seeding ability. Taken together, FABP3 could be a potential therapeutic target against αSyn propagation in synucleinopathies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

α-synuclein (αSyn) is a protein known to form intracellular aggregates during the manifestation of Parkinson's disease. Previously, it was shown that αSyn aggregation was strongly suppressed in the midbrain region of mice that did not possess the gene encoding the lipid transport protein fatty acid binding protein 3 (FABP3). An interaction between these two proteins was detected in vitro, suggesting that FABP3 may play a role in the aggregation and deposition of αSyn in neurons. To characterize the molecular mechanisms that underlie the interactions between FABP3 and αSyn that modulate the cellular accumulation of the latter, in this report, we used in vitro fluorescence assays combined with fluorescence microscopy, transmission electron microscopy, and quartz crystal microbalance assays to characterize in detail the process and consequences of FABP3-αSyn interaction. We demonstrated that binding of FABP3 to αSyn results in changes in the aggregation mechanism of the latter; specifically, a suppression of fibrillar forms of αSyn and also the production of aggregates with an enhanced cytotoxicity toward mice neuro2A cells. Because this interaction involved the C-terminal sequence region of αSyn, we tested a peptide derived from this region of αSyn (αSynP130-140) as a decoy to prevent the FABP3-αSyn interaction. We observed that the peptide competitively inhibited binding of αSyn to FABP3 in vitro and in cultured cells. We propose that administration of αSynP130-140 might be used to prevent the accumulation of toxic FABP3-αSyn oligomers in cells, thereby preventing the progression of Parkinson's disease., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Oligomerization and/or aggregation of α-synuclein (α-Syn) triggers α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies. It is known that α-Syn can spread in the brain like prions; however, the mechanism remains unclear. We demonstrated that fatty acid binding protein 3 (FABP3) promotes propagation of α-Syn in mouse brain. Animals were injected with mouse or human α-Syn pre-formed fibrils (PFF) into the bilateral substantia nigra pars compacta (SNpc). Two weeks after injection of mouse α-Syn PFF, wild-type (WT) mice exhibited motor and cognitive deficits, whereas FABP3 knock-out ( Fabp3 -/- ) mice did not. The number of phosphorylated α-Syn (Ser-129)-positive cells was significantly decreased in Fabp3 -/- mouse brain compared to that in WT mice. The SNpc was unilaterally infected with AAV-GFP/FABP3 in Fabp3 -/- mice to confirm the involvement of FABP3 in the development of α-Syn PFF toxicity. The number of tyrosine hydroxylase (TH)- and phosphorylated α-Syn (Ser-129)-positive cells following α-Syn PFF injection significantly decreased in Fabp3 -/- mice and markedly increased by AAV-GFP/FABP3 infection. Finally, we confirmed that the novel FABP3 inhibitor MF1 significantly antagonized motor and cognitive impairments by preventing α-Syn spreading following α-Syn PFF injection. Overall, FABP3 enhances α-Syn spreading in the brain following α-Syn PFF injection, and the FABP3 ligand MF1 represents an attractive therapeutic candidate for α-synucleinopathy.

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.

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)