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

Accumulation and aggregation of alpha-synuclein (alpha Syn) trigger 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 alpha Syn neurotoxicity in SNpc and motor impairments after intranigral injection of alpha Syn fibrils. However, the temporal profile of alpha Syn fibril spread and their toxicity remains unclear. In the present study, we investigated the temporal profile of alpha Syn fibril spread and its toxicity, which induces intracellular fibril formation. Monomeric and fibrillar alpha Syn assemblies were labeled with ATTO550 to distinguish the exogenous form from the endogenous species and injected into bilateral striatum in Fabp3(+/+) (wild type) and Fabp3(-/-) mice. Accumulation of both monomeric and fibrillar exogenous alpha Syn in the SNpc was drastically decreased in Fabp3(-/-) mice compared to that in the Fabp3(+/+) counterparts. Deletion of Fabp3 also prevented exogenous alpha Syn fibril-induced seeding of the endogenous alpha Syn into aggregates containing phosphorylated and filamentous forms in the SNpc. Consistent with these results, loss of dopaminergic neurons and subsequent impaired motor behavior were attenuated in Fabp3(-/-) mice. These results highlight the crucial role of FABP3 in pathogenic alpha Syn accumulation and its seeding ability. Taken together, FABP3 could be a potential therapeutic target against alpha Syn propagation in synucleinopathies.

Automated summary

This study demonstrates the crucial role of fatty acid-binding protein 3 (FABP3) in pathogenic alpha-synuclein accumulation and its seeding ability, showing that the deletion of FABP3 can reduce the accumulation of exogenous alpha-synuclein in the substantia nigra pars compacta and attenuate motor impairments. These results suggest that FABP3 could be a potential therapeutic target against alpha-synuclein propagation in synucleinopathies.