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

• Main Authors: Yasushi Yabuki, Kazuya Matsuo, Ichiro Kawahata, Naoya Fukui, Tomohiro Mizobata, Yasushi Kawata, Yuji Owada, Norifumi Shioda, Kohji Fukunaga
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: International Journal of Molecular Sciences
• Subjects: α-synuclein; fatty acid binding protein 3; α-synuclein propagation; α-synucleinopathy
• Online Access: https://www.mdpi.com/1422-0067/21/6/2230

Oligomerization and/or aggregation of &#945;-synuclein (&#945;-Syn) triggers &#945;-synucleinopathies such as Parkinson&#8217;s disease and dementia with Lewy bodies. It is known that &#945;-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 &#945;-Syn in mouse brain. Animals were injected with mouse or human &#945;-Syn pre-formed fibrils (PFF) into the bilateral substantia nigra pars compacta (SNpc). Two weeks after injection of mouse &#945;-Syn PFF, wild-type (WT) mice exhibited motor and cognitive deficits, whereas FABP3 knock-out (<i>Fabp3</i>^{&#8722;/&#8722;}) mice did not. The number of phosphorylated &#945;-Syn (Ser-129)-positive cells was significantly decreased in <i>Fabp3</i>^{&#8722;/&#8722;} mouse brain compared to that in WT mice. The SNpc was unilaterally infected with AAV-GFP/FABP3 in <i>Fabp3</i>^{&#8722;/&#8722;} mice to confirm the involvement of FABP3 in the development of &#945;-Syn PFF toxicity. The number of tyrosine hydroxylase (TH)- and phosphorylated &#945;-Syn (Ser-129)-positive cells following &#945;-Syn PFF injection significantly decreased in <i>Fabp3</i>^{&#8722;/&#8722;} 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 &#945;-Syn spreading following &#945;-Syn PFF injection. Overall, FABP3 enhances &#945;-Syn spreading in the brain following &#945;-Syn PFF injection, and the FABP3 ligand MF1 represents an attractive therapeutic candidate for &#945;-synucleinopathy.