β-Synuclein occurs in vivo in lipid-associated oligomers and forms hetero-oligomers with α-synuclein

alpha-synuclein (alpha S) and beta-synuclein (beta S) are homologous proteins implicated in Parkinson's disease and related synucleinopathies. While alpha S is neurotoxic and its aggregation and deposition in Lewy bodies is related to neurodegeneration, beta S is considered as a potent inhibitor of alpha S aggregation and toxicity. No mechanism for the neuroprotective role of beta S has been described before. Here, we report that similar to alpha S, beta S normally occurs in lipid-associated, soluble oligomers in wild-type (WT) mouse brains. We partially purified beta S and alpha S proteins from whole mouse brain by size exclusion followed by ion exchange chromatography and found highly similar elution profiles. Using this technique, we were able to partially separate beta S from alpha S and further separate beta S monomer from its own oligomers. Importantly, we show that although alpha S and beta S share high degree of similarities, beta S oligomerization is not affected by increasing cellular levels of polyunsaturated fatty acids (PUFAs), while alpha S oligomerization is dramatically enhanced by PUFA. We show the in vivo occurrence of hetero-oligomers of alpha S and beta S and suggest that beta S expression inhibits PUFA-enhanced alpha S oligomerization by forming hetero-oligomers up to a quatramer that do not further propagate.