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

ABSTRACT: Oligomerization and/or aggregation of ?-synuclein (?-Syn) triggers ?-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies. It is known that ?-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 ?-Syn in mouse brain. Animals were injected with mouse or human ?-Syn pre-formed fibrils (PFF) into the bilateral substantia nigra pars compacta (SNpc). Two weeks after injection of mouse ?-Syn PFF, wild-type (WT) mice exhibited motor and cognitive deficits, whereas FABP3 knock-out (Fabp3-/-) mice did not. The number of phosphorylated ?-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 ?-Syn PFF toxicity. The number of tyrosine hydroxylase (TH)- and phosphorylated ?-Syn (Ser-129)-positive cells following ?-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 ?-Syn spreading following ?-Syn PFF injection. Overall, FABP3 enhances ?-Syn spreading in the brain following ?-Syn PFF injection, and the FABP3 ligand MF1 represents an attractive therapeutic candidate for ?-synucleinopathy.

SUBMITTER: Yabuki Y 

PROVIDER: S-EPMC7139546 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature