β-III Tubulin Fragments Inhibit α-Synuclein Accumulation in Models of Multiple System Atrophy

Background: Neuronal and oligodendrocytic aggregation of insoluble -synuclein contributes to neuropathology in multiple system atrophy. Results: -Synuclein binds directly to -III tubulin. A fragment carrying the -synuclein-binding site inhibited -synuclein-III tubulin complex formation and intracellular -synuclein accumulation. Conclusion: Inhibition of -synuclein binding to -III tubulin may be an effective strategy for preventing -synuclein accumulation. Significance: Small -III tubulin fragments may inhibit neurodegeneration in multiple system atrophy.Multiple system atrophy (MSA) is a neurodegenerative disease caused by -synuclein aggregation in oligodendrocytes and neurons. Using a transgenic mouse model overexpressing human -synuclein in oligodendrocytes, we previously demonstrated that oligodendrocytic -synuclein inclusions induce neuronal -synuclein accumulation and progressive neuronal degeneration. -Synuclein binds to -III tubulin, leading to the neuronal accumulation of insoluble -synuclein in an MSA mouse model. The present study demonstrates that -synuclein co-localizes with -III tubulin in the brain tissue from patients with MSA and MSA model transgenic mice as well as neurons cultured from these mice. Accumulation of insoluble -synuclein in MSA mouse neurons was blocked by the peptide fragment -III tubulin (residues 235-282). We have determined the -synuclein-binding domain of -III tubulin and demonstrated that a short fragment containing this domain can suppress -synuclein accumulation in the primary cultured cells. Administration of a short -synuclein-binding fragment of -III tubulin may be a novel therapeutic strategy for MSA.