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.

Automated summary

The specific inhibitor MF6 can reduce α-Syn aggregation, improve cell viability, motor function, and reduce oxidative stress and inflammation levels. It also improves cerebellar function and neuron morphology through regulating endocytosis, showing potential for the treatment of multiple system atrophy (MSA).