Suppression of α-synuclein propagation after intrastriatal injection in FABP3 null mice

Kazuya Matsuo (1) , Ichiro Kawahata (1) , Ronald Melki (2, 3) , Luc Bousset (2, 3) , Yuji Owada (4) , Kohji Fukunaga (1)

1 Tohoku University [Sendai]
2 CNRS - Centre National de la Recherche Scientifique
3 MIRCEN - Service MIRCEN
4 School of Engineering [Tohoku Univ]

Accumulation and aggregation of α-synuclein (αSyn) triggers neuronal loss in the substantia nigra pars compacta (SNpc) which in turn causes motor symptoms in Parkinson’s disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3), an intracellular fatty acid carrier protein, enhances αSyn neurotoxicity in the SNpc and motor impairments after intranigral injection of αSyn fibrils. However, temporal spreading profile of αSyn fibrils and those toxicity remains unclear. In the presentstudy, we investigated the temporal profile of αSyn fibrils and its toxicity inducing intracellular fibril formation. Monomeric and fibrillar aSyn assemblies were labelled with ATTO550 to distinguish exogenous from endogenous species and injected into bilateral striatum in Fabp3$^{+/+}$ (wild type) and Fabp3$^{-/-}$ mice. Accumulation of both monomeric and fibrillar exogenous αSyn in the SNpc was drastically decreased in Fabp3$^{-/-}$ mice compared to Fabp3$^{+/+}$ counterparts. Fabp3 deletion also prevented exogenous αSyn fibrils-induced seeding of endogenous αSyn into aggregation containing phosphorylated and filament forms in the SNpc. Consistent with these results, loss of dopaminergic neurons and the following impaired motor behaviours were attenuated in Fabp3$^{-/-}$ mice. These results highlight crucial role of FABP3 in pathogenic αSyn accumulation and its seeding ability. Taken together, FABP3 could be a potential therapeutic target against αSyn propagation in synucleinopathies.

Keywords: dementia with Lewy bodies; fatty acid-binding protein; Lewy body; Lewy neurite; Parkinson's disease; substantia nigra pars compacta; phosphorylated αSyn; tyrosine hydroxylase; ventral tegmental area; α-synuclein

Domains: Human health and pathology

Kazuya Matsuo, Ichiro Kawahata, Ronald Melki, Luc Bousset, Yuji Owada, et al.. Suppression of α-synuclein propagation after intrastriatal injection in FABP3 null mice. Brain Research, 2021, 1760, pp.147383. ⟨10.1016/j.brainres.2021.147383⟩. ⟨cea-03174556⟩