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

Abstract

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.

Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor

“…Chronic administration (at least once a day for seven consecutive weeks) of MF1 (1.0 mg/kg, p.o.) did not affect motor and cognitive function in mice [ 23 , 26 ]. While the tolerance and withdrawal of MF1 should be analyzed, we hope that MF1 may be a safer alternative for long-term therapy.…”

“…We originally developed MF1 as therapeutic candidate for α-synucleinopathies [ 23 , 26 ]. MF1 attenuates aggregation and spreading of α-synuclein by preventing interactions between FABP3 and α-synuclein [ 23 , 26 ], suggesting that MF1 has the potential for early treatment of α-synucleinopathies.…”

“…We originally developed MF1 as therapeutic candidate for α-synucleinopathies [ 23 , 26 ]. MF1 attenuates aggregation and spreading of α-synuclein by preventing interactions between FABP3 and α-synuclein [ 23 , 26 ], suggesting that MF1 has the potential for early treatment of α-synucleinopathies. Patients with DLB cause seizures (14.7%) and myoclonus (58.1%) after disease onset, indicating that the seizure incidence rates are approximately 10-fold, relative to healthy controls [ 42 , 43 ].…”

“…FABP3 null mice show resistance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal toxicity and PD-like motor deficits [ 22 ]. FABP3 deficiency also prevents the spreading of α-synucleinopathy-like pathologies following the injection of α-synuclein preformed fibril (PFF) in the mouse brain [ 23 ] and uptake into dopaminergic neurons [ 24 ]. Moreover, we have succeeded in producing a novel FABP3 ligand, MF1 (4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid), which has a high affinity for FABP3 [ 25 , 26 ].…”

“…Moreover, we have succeeded in producing a novel FABP3 ligand, MF1 (4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid), which has a high affinity for FABP3 [ 25 , 26 ]. MF1 significantly attenuates loss of dopaminergic neurons, behavioral impairments and α-synucleinopathy-like pathologies observed in MPTP-treated and/or α-synuclein PFF injected mice [ 23 , 26 ]. These results suggest that FABP3 is a potential molecular target producing novel therapeutics for α-synucleinopathies.…”