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Fatty Acid Binding Protein 3 Enhances the Spreading and Toxicity of α-Synuclein in Mouse Brain

1
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan
2
Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-8555, Japan
3
Department of Chemistry and Biotechnology, Graduate School of Engineering Tottori University, Tottori 680-8550, Japan
4
Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Tottori 680-8550, Japan
5
Department of Organ Anatomy, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8578, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(6), 2230; https://doi.org/10.3390/ijms21062230
Received: 30 January 2020 / Revised: 7 March 2020 / Accepted: 17 March 2020 / Published: 23 March 2020
(This article belongs to the Special Issue Precision Medicine and Therapy for Neurodegenerative Disorders)
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. View Full-Text
Keywords: α-synuclein; fatty acid binding protein 3; α-synuclein propagation; α-synucleinopathy α-synuclein; fatty acid binding protein 3; α-synuclein propagation; α-synucleinopathy
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Yabuki, Y.; Matsuo, K.; Kawahata, I.; Fukui, N.; Mizobata, T.; Kawata, Y.; Owada, Y.; Shioda, N.; Fukunaga, K. Fatty Acid Binding Protein 3 Enhances the Spreading and Toxicity of α-Synuclein in Mouse Brain. Int. J. Mol. Sci. 2020, 21, 2230.

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