The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease.
Accumulation of misfolded proteins as insoluble aggregates occurs in several neurodegenerative diseases. In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), alpha-synuclein (alpha S) accumulates in insoluble inclusions. To identify soluble alpha S oligomers that precede insoluble aggregates, we probed the cytosols of mesencephalic neuronal (MES) cells, normal and alpha S-transgenic mouse brains, and normal, PD, and DLB human brains. All contained highly soluble oligomers of alpha S whose detection was enhanced by delipidation. Exposure of living MES neurons to polyunsaturated fatty acids (PUFAs) increased alpha S oligomer levels, whereas saturated FAs decreased them. PUFAs directly promoted oligomerization of recombinant alphaS. Transgenic mice accumulated soluble oligomers with age. PD and DLB brains had elevated amounts of the soluble, lipid-dependent oligomers. We conclude that alpha S interacts with PUFAs in vivo to promote the formation of highly soluble oligomers that precede the insoluble alpha S aggregates associated with neurodegeneration.
Sharon
Ronit
R
Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02215, USA.
Bar-Joseph
Ifat
I
Frosch
Matthew P
MP
Walsh
Dominic M
DM
Hamilton
James A
JA
Selkoe
Dennis J
DJ
D000367:Age Factors; D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002460:Cell Line; D003600:Cytosol / Q000737:chemistry; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism*; D046911:Macromolecular Substances; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D051843:Synucleins; D051844:alpha-Synuclein
D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein