Pharmacological inhibition of FABP7 by MF 6 counteracts cerebellum dysfunction in an experimental multiple system atrophy mouse model

Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disease characterized by the accumulation of misfolded & alpha;-synuclein (& alpha;Syn) in glial cells, leading to the formation of glial cytoplasmic inclusions (GCI). We previous found that glial fatty acid-binding protein 7 (FABP7) played a crucial role in alpha-synuclein (& alpha;Syn) aggregation and toxicity in oligodendrocytes, inhibition of FABP7 by a specific inhibitor MF 6 reduced & alpha;Syn aggregation and enhanced cell viability in cultured cell lines and mouse oligodendrocyte progenitor cells. In this study we investigated whether MF 6 ameliorated & alpha;Syn-associated pathological processes in PLP-h & alpha;Syn transgenic mice (PLP-& alpha;Syn mice), a wildly used MSA mouse model with overexpressing & alpha;Syn in oligodendroglia under the proteolipid protein (PLP) promoter. PLP-& alpha;Syn mice were orally administered MF6 (0.1, 1 mg & BULL;kg(-1) & BULL;d(-1)) for 32 days starting from the age of 6 months. We showed that oral administration of MF 6 significantly improved motor function assessed in a pole test, and reduced & alpha;Syn aggregation levels in both cerebellum and basal ganglia of PLP-& alpha;Syn mice. Moreover, MF 6 administration decreased oxidative stress and inflammation levels, and improved myelin levels and Purkinje neuron morphology in the cerebellum. By using mouse brain tissue slices and & alpha;Syn aggregates-treated KG-1C cells, we demonstrated that MF 6 reduced & alpha;Syn propagation to Purkinje neurons and oligodendrocytes through regulating endocytosis. Overall, these results suggest that MF 6 improves cerebellar functions in MSA by inhibiting & alpha;Syn aggregation and propagation. We conclude that MF 6 is a promising compound that warrants further development for the treatment of MSA.