Targeting the N-terminus of α-synuclein Monomer Reduces Fibril-induced Aggregation in the Brain

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Abstract Background Removing α-synuclein aggregates or preventing their formation constitutes a plausible strategy against Parkinson’s disease (PD). As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein (aSyn), interferes with fibril nucleation and reduces aSyn aggregates in vitro and in a fruit fly model of A53T aSyn toxicity. Here we tested whether AS69 could also reduce aSyn pathology in mammalian neurons and in mouse brain. Methods Primary mouse neurons were exposed to pre-formed fibrils (PFF) of human WT aSyn or PFF was injected into the striatum of A30P-aSyn transgenic mice to induce aSyn pathology. Densities of phospho-aSyn positive somatic inclusions and dystrophic neurites, degeneration of dopaminergic axon terminals in the striatum and the glial response were determined. Results PFF were readily taken up by primary mouse neurons, and AS69 did not alter PFF uptake. aSyn pathology, as determined by phospho-aSyn staining, was much more pronounced 72 h after PFF addition than after 24 h, and was reduced by AS69. In the striatum, PFF increased aSyn pathology, induced degeneration of dopaminergic axon terminals and glial activation at 90 days after PFF injection. The extent of terminal loss correlated with the density of dystrophic neurites, but not with the number of somatic inclusions. Co-injection of AS69 with PFF abrogated the induction of somatic inclusions and dystrophic neurites, reduced the loss of dopaminergic axon terminals and the reaction of astroglia, but not the effect on microglia. Conclusion AS69, an aSyn monomer-binding protein, reduces aSyn pathology and loss of dopaminergic terminals in primary neurons and in a mouse model. Therefore, our data suggests, that small aSyn-monomer binding proteins, such as AS69, could be promising new therapeutic approaches against Parkinson's disease.

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