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

Yasushi Yabuki,Naoya Fukui,Yuji Owada,Yasushi Kawata,Tomohiro Mizobata,Norifumi Shioda,Kohji Fukunaga,Kazuya Matsuo,Ichiro Kawahata

doi:10.3390/ijms21062230

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.

Highlights

Introduction αSynuclein (α-Syn), a 140-amino acid protein, is enriched in the synaptic vesicle fraction [1]
We identified the following in α-Syn pre-formed fibrils (PFF) injected mice: 1) fatty acid binding protein 3 (FABP3) deficiency antagonized the propagation of α-Syn, 2) FABP3 mediated α-Syn toxicity after α-Syn PFF injection in tyrosine hydroxylase (TH)-positive dopaminergic neurons, and 3) FABP3 inhibitor MF1 administration attenuated motor and cognitive deficits induced by α-Syn toxicity
Grassi et al have recently reported that non-fibrillar phosphorylated α-Syn derived from its PFF evokes mitochondrial cytochrome C release and oxidative stress [51], suggesting that oxidative stress triggers the conversion of endogenous normal α-Syn to a pathological phosphorylated form and in turn promotes its propagation throughout the entire brain

Summary

Introduction

Introduction αSynuclein (α-Syn), a 140-amino acid protein, is enriched in the synaptic vesicle fraction [1]. Its misfolding causes the formation of β-sheet-rich fibrils, which can convert to Lewy bodies (LBs) and Lewy neurites (LNs) and are causative for α-synucleinopathies, including Parkinson’s disease (PD), dementia with LBs (DLB), and multiple system atrophy (MSA) [2,3,4]. Aggregated α-Syn is observed in transplanted dopaminergic neurons in the postmortem PD brain following cell transplantation therapy [15,16], suggesting that misfolded α-Syn can propagate from cell to cell and in turn aggregate normal endogenous α-Syn. Unilateral injection of mouse α-Syn pre-formed fibrils (PFF) into the dorsal striatum and/or somatosensory cortex develops and propagates Lewy-like phosphorylated α-Syn in the whole brain, including contralateral areas in both wild-type (WT) and human A53T-mutated mice [17,18]. Potential mechanisms underlying the prion-like propagation of α-Syn have been proposed [23,24,25]; molecular mechanisms involved in this propagation remain controversial

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Conclusion