Beta-synuclein occurs in vivo in lipid-associated oligomers and forms hetero-oligomers with alpha-synuclein.
Alpha-synuclein (alphaS) and beta-synuclein (betaS) are homologous proteins implicated in Parkinson's disease and related synucleinopathies. While alphaS is neurotoxic and its aggregation and deposition in Lewy bodies is related to neurodegeneration, betaS is considered as a potent inhibitor of alphaS aggregation and toxicity. No mechanism for the neuroprotective role of betaS has been described before. Here, we report that similar to alphaS, betaS normally occurs in lipid-associated, soluble oligomers in wild-type (WT) mouse brains. We partially purified betaS and alphaS 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 betaS from alphaS and further separate betaS monomer from its own oligomers. Importantly, we show that although alphaS and betaS share high degree of similarities, betaS oligomerization is not affected by increasing cellular levels of polyunsaturated fatty acids (PUFAs), while alphaS oligomerization is dramatically enhanced by PUFA. We show the in vivo occurrence of hetero-oligomers of alphaS and betaS and suggest that betaS expression inhibits PUFA-enhanced alphaS oligomerization by forming hetero-oligomers up to a quatramer that do not further propagate.
Israeli
Eitan
E
Department of Cellular Biochemistry and Human Genetics, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Sharon
Ronit
R
D000818:Animals; D001921:Brain / Q000378:metabolism; D002461:Cell Line, Transformed; D002852:Chromatography, Ion Exchange / Q000379:methods; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008055:Lipids; D046911:Macromolecular Substances; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects; D051844:alpha-Synuclein / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*; D051846:beta-Synuclein / Q000737:chemistry* / Q000378:metabolism*
D005231:Fatty Acids, Unsaturated; D008055:Lipids; D046911:Macromolecular Substances; D051844:alpha-Synuclein; D051846:beta-Synuclein