Altered Fatty Acid Composition of Dopaminergic Neurons Expressing α-Synuclein and Human Brains with α-Synucleinopathies

Abstract

α-Synuclein (αS) is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson's disease (PD) and the related disorder, dementia with Lewy bodies (DLB). A central question about the role of αS in the pathogenesis of PD and DLB concerns how this normally soluble protein assembles into insoluble aggregates associated with neuronal dysfunction. We recently detected highly soluble oligomers of αS in normal brain supernatants and observed their augmentation in PD and DLB brains. Further, we found that polyunsaturated fatty acids (PUFAs) enhanced αS oligomerization in intact mesencephalic neuronal cells. We now report the presence of elevated PUFA levels in PD and DLB brain soluble fractions. Higher PUFA levels were also detected in the supernatants and high-speed membrane fractions of neuronal cells over-expressing wild-type or PD-causing mutant αS. This increased PUFA content in the membrane fraction was accompanied by increased membrane fluidity in the αS overexpressing neurons. In accord, membrane fluidity and the levels of certain PUFAs were decreased in the brains of mice genetically deleted of αS. Together with our earlier observations, these results suggest that αS-PUFA interactions help regulate neuronal PUFA levels as well as the oligomerization state of αS, both normally and in human synucleinopathies. α-Synuclein (αS) is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson's disease (PD) and the related disorder, dementia with Lewy bodies (DLB). A central question about the role of αS in the pathogenesis of PD and DLB concerns how this normally soluble protein assembles into insoluble aggregates associated with neuronal dysfunction. We recently detected highly soluble oligomers of αS in normal brain supernatants and observed their augmentation in PD and DLB brains. Further, we found that polyunsaturated fatty acids (PUFAs) enhanced αS oligomerization in intact mesencephalic neuronal cells. We now report the presence of elevated PUFA levels in PD and DLB brain soluble fractions. Higher PUFA levels were also detected in the supernatants and high-speed membrane fractions of neuronal cells over-expressing wild-type or PD-causing mutant αS. This increased PUFA content in the membrane fraction was accompanied by increased membrane fluidity in the αS overexpressing neurons. In accord, membrane fluidity and the levels of certain PUFAs were decreased in the brains of mice genetically deleted of αS. Together with our earlier observations, these results suggest that αS-PUFA interactions help regulate neuronal PUFA levels as well as the oligomerization state of αS, both normally and in human synucleinopathies. α-Synuclein (αS), 1The abbreviations used are: αSα-synucleinPDParkinson's diseaseDLBdementia with Lewy bodiesPUFApolyunsaturated fatty acidsGCgas chromatographyMSmass spectrometrySECsize exclusion chromatographyMESmesencephalic neuronalwtwild-typeSFAsaturated fatty acidsMUFAmonounsaturated fatty acids. a 140-residue protein implicated in both familial and sporadic Parkinson's disease (PD), occurs principally as a cytoplasmic polypeptide in neurons and is localized in part to presynaptic terminals (1.George J.M. Jin H. Woods W.S. Clayton D.F. Neuron. 1995; 15: 361-372Abstract Full Text PDF PubMed Scopus (732) Google Scholar). In general, brain αS is highly soluble, and purified recombinant αS is reported to have a disordered random coil structure in solution (2.Weinreb P.H. Zhen W. Poon A.W. Conway K.A. Lansbury Jr., P.T. Biochemistry. 1996; 35: 13709-13715Crossref PubMed Scopus (1326) Google Scholar). A wide array of factors has been found to induce the aggregation of αS under experimental conditions. These include PD-causing missense mutations in αS (3.Narhi L. Wood S.J. Steavenson S. Jiang Y. Wu G.M. Anafi D. Kaufman S.A. Martin F. Sitney K. Denis P. Louis J.C. Wypych J. Biere A.L. Citron M. J. Biol. Chem. 1999; 274: 9843-9846Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar, 4.Conway K.A. Lee S.J. Rochet J.C. Ding T.T. Williamson R.E. Lansbury Jr., P.T. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 571-576Crossref PubMed Scopus (1347) Google Scholar, 5.Conway K.A. Harper J.D. Lansbury P.T. Nat. Med. 1998; 4: 1318-1320Crossref PubMed Scopus (1271) Google Scholar), mitochondrial inhibitors and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (6.Lee H.J. Shin S.Y. Choi C. Lee Y.H. Lee S.J. J. Biol. 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Neurosci. 2001; 21: 8053-8061Crossref PubMed Google Scholar, 13.Kim K.S. Choi S.Y. Kwon H.Y. Won M.H. Kang T.C. Kang J.H. Free Radic. Biol. Med. 2002; 32: 544-550Crossref PubMed Scopus (56) Google Scholar), αS phosphorylation (14.Fujiwara H. Hasegawa M. Dohmae N. Kawashima A. Masliah E. Goldberg M.S. Shen J. Takio K. Iwatsubo T. Nat. Cell Biol. 2002; 4: 160-164Crossref PubMed Scopus (162) Google Scholar), and fatty acids, whether within phospholipids (15.Perrin R.J. Woods W.S. Clayton D.F. George J.M. J. Biol. Chem. 2001; 276: 41958-41962Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar) or as free fatty acids (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). Interestingly, some of the factors that can induce αS aggregation experimentally have been found to be associated with PD, e.g. αS mutations, mitochondrial complex I dysfunction, proteosomal dysfunction, and oxidative stress. Other factors, including free fatty acid composition, have not been comprehensively studied in the brains of patients with PD and other synucleinopathies. α-synuclein Parkinson's disease dementia with Lewy bodies polyunsaturated fatty acids gas chromatography mass spectrometry size exclusion chromatography mesencephalic neuronal wild-type saturated fatty acids monounsaturated fatty acids. We recently obtained evidence that αS can directly bind fatty acids (17.Sharon R. Goldberg M.S. Bar-Josef I. Betensky R.A. Shen J. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9110-9115Crossref PubMed Scopus (266) Google Scholar) and can form highly soluble oligomers in response to the treatment of cultured neurons with polyunsaturated fatty acids (PUFA) (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). Further, we observed a pool of soluble αS oligomers that is detectable only after biochemical treatments that remove fatty acids and other lipids (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, 17.Sharon R. Goldberg M.S. Bar-Josef I. Betensky R.A. Shen J. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9110-9115Crossref PubMed Scopus (266) Google Scholar). These highly soluble, lipid-associated oligomers were detected in mesencephalic neuronal (MES) cells expressing human αS, in the brains of normal and human αS transgenic mice, and in the brains of humans with PD and the related disorder, dementia with Lewy bodies (DLB). We also showed that the formation of soluble αS oligomers is directly regulated by fatty acids in intact cells, with specific enhancement of the oligomers by PUFAs and inhibition by saturated FAs (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). These findings have now led us to search systematically for evidence of a correlation between αS oligomerization and endogenous PUFA composition. First, we find that the relative amounts of PUFAs in the oligomer-rich soluble fraction of human brains with PD and DLB are higher than in those of age-matched normal brains. Second, higher PUFA levels are detected in the cytosols of normal mouse than αS-null mouse brain and in the cytosols of cells expressing human αS than in cells. the PUFA in the human cells is accompanied by PUFA in membrane fractions we higher membrane fluidity in of cells than in the cells and in the of normal than αS-null mouse brains. αS-null mouse in the was mice were obtained were experimental we only used brains of mice that were and in our than the mice that been to of the brains in the PD, and that we studied in an earlier (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar) and brains to of these in and were as (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). and was as (17.Sharon R. Goldberg M.S. Bar-Josef I. Betensky R.A. Shen J. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9110-9115Crossref PubMed Scopus (266) Google Scholar). high-speed cytosols and high-speed membrane between and were membrane were and in were to the membrane of high-speed cytosols or were and for FAs the with and in is to the with with in for in and a with fatty acids is into a gas with a an a and an by a used a with as the of the were as to in were by with and by of was high-speed and the fractions were and as (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). K. T. S. N. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), were with by with for in the were a gas a mass with an was to and was a and were in the with in was and and in a acids and were to the in their mass and their of high-speed that between and were and and used within fluidity was acid a was a and the were to the with some were with an was with and the was a were with in and in a of was for with were and in in and to of membrane with were and the of to were in mouse of brain membrane with brains. in cells, of membrane we used to the PD and DLB the of human and the and neuronal cells cells. We for fatty acid and the of the and were used to the levels of these fatty acids between of the of the of fatty acids to within these are and a of was We reported that αS can bind FAs in (17.Sharon R. Goldberg M.S. Bar-Josef I. Betensky R.A. Shen J. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9110-9115Crossref PubMed Scopus (266) Google Scholar), that PUFAs saturated FAs the formation of soluble αS oligomers both in and in intact cells (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar), and that the levels of soluble and insoluble αS oligomers are elevated in the brains of humans αS in PD and DLB (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). These findings led us to that the increased levels of soluble αS oligomers in PD and DLB brains be associated with in the of endogenous brain We that overexpressing αS in neuronal cells their endogenous composition. of the of PD and DLB the of the high-speed cytosols brains of the PD, and age-matched in been for their levels of soluble αS and these levels were increased in the supernatants of the PD and DLB brains (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). and PUFAs were by in the high-speed soluble fractions of We observed a highly in PUFA in the PD and DLB a in acid levels of for PD, for an in acid levels of for PD, for and an in acid levels for PD in in DLB not Other PUFAs were not were in the of and in these brain These results an between PUFA in the soluble fractions of PD and DLB brains and the of highly soluble αS oligomers in these fractions (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). of αS in PUFA in and increased αS levels were associated with increased PUFA levels in the soluble fractions of PD and DLB we whether αS induce of PUFA composition. cytosols and membrane were neuronal cells that were or with or human αS. of were the of αS in these cells, between and (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar) These of and PUFAs were in with that the presence of αS oligomers in the high-speed cytosols We observed a of PUFAs in the cytosols of the cells. In cells, PUFAs were by our and αS these PUFAs to detectable In the levels of saturated and monounsaturated FAs were not in the a and occurs in soluble oligomers in the of human and cells. of high-speed cytosols cells their of between and (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar), were for and to and αS R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google for In a (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar), we showed that neurons with with PUFAs αS oligomerization and In of the results an between αS and PUFA we now whether PUFA are associated with the αS or whether a or other is We the high-speed cytosols of human neurons by the of We found that cells in with acid or acid not these specific PUFAs in their cytosols in the of the neurons not in the neurons In an for in other we only in the levels of those FAs that been in the of the neurons. This that enhancement of soluble αS levels in a neuronal to specific of those fatty acids in the of the We a to high-speed membrane fractions between and mouse brains that were by for αS of mouse brain αS was found in this high-speed membrane fraction (17.Sharon R. Goldberg M.S. Bar-Josef I. Betensky R.A. Shen J. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9110-9115Crossref PubMed Scopus (266) Google Scholar). We of PUFA in the high-speed membrane fractions of the cells. This a of PUFAs in the of the and neurons the cells in with the in soluble αS oligomers in the cytosols of the (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). we observed in the and and and in detectable amounts in both and in Interestingly, the levels of the acid were in the and overexpressing cells Other detectable by our were as were In to this of we the of FAs in a and our human αS and human αS We observed in PUFA content in both the and αS expressing cells of and This was accompanied by in content of and were in These results that the of human αS in mesencephalic neurons results in relative in PUFA relative levels the of relative were detected in the of FAs in αS cells with the cells. αS in fluidity is by the and PUFAs in S. A. and Google Scholar). in the amounts of PUFAs to in membrane relative in membrane fluidity S. A. and Google Scholar, S. S. 2002; PubMed Scopus Google Scholar, K.A. Martin A. J.A. J. Neurosci. 2000; PubMed Scopus Google Scholar). In of the in PUFA we observed in the of neurons and human brains and as well as the of αS with (17.Sharon R. Goldberg M.S. Bar-Josef I. Betensky R.A. Shen J. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9110-9115Crossref PubMed Scopus (266) Google Scholar, H. S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. L. H. A. M. U. H. A. E. C. J. Neurosci. 2000; PubMed Google Scholar, P.H. M.S. R. M. J. Biol. 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In with our results in human brains and neurons αS we detected higher relative PUFA levels in the presence of and αS than in their acid and acid were detected in the cytosols of αS not in and were between the in certain other PUFAs and in the not this correlation between the presence of αS and PUFA we the high-speed cytosols of both wild-type and brains and the of those fractions found to αS oligomers in the mice of fractions results a correlation between the presence of αS and the presence of certain and were detected only in the fractions αS and not in the fractions of the brains other as and that were in amounts in the brain cytosols and in the brain cytosols were not detectable in the fractions. We detected of or in the brain cytosols or the fractions not We the brain membrane fluidity of the αS and brain between and were in mice of between and and to the membrane fluidity fluidity for the were obtained in the with the This is in with the higher membrane fluidity we observed in cells over-expressing αS we the of the mouse brain membrane was in the relative of PUFAs in the in to the increased PUFA content observed in the cells. the other we observed an of in the of fatty acids protein in the high-speed of brains with wild-type not fluidity for wild-type and αS-null mouse in a In a of (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, 17.Sharon R. Goldberg M.S. Bar-Josef I. Betensky R.A. Shen J. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9110-9115Crossref PubMed Scopus (266) Google Scholar), we have of the of neuronal α-synuclein with fatty acids under normal and We observed that recombinant αS is of FAs in and that a pool of highly soluble αS oligomers normally in cultured neurons and the brain and can be by that bind fatty acids (17.Sharon R. Goldberg M.S. Bar-Josef I. Betensky R.A. Shen J. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9110-9115Crossref PubMed Scopus (266) Google Scholar). we showed that the of αS into soluble oligomers is enhanced by the of intact neurons to levels of of the oligomers is by of the cells to (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). These of FAs αS state be as PUFAs enhanced the oligomerization of recombinant αS in we these findings by that in the state of a human the of αS, including as soluble is associated with in brain PUFA composition. we the of certain PUFAs in the high-speed soluble fraction of brains with PD and the fraction in we found of soluble αS oligomers in these (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). We observed a of acid in PD and DLB brain cytosols and also of acid in PD with levels in age-matched brain In was a in the acid in PD and DLB brains. to the PUFA with αS we in mesencephalic neuronal cells that human αS or including and in the of cells expressing human αS, with cells expressing levels of endogenous αS. In this the of certain PUFAs was for the levels in the of cells was by human αS these PUFAs detectable and A specific correlation between PUFA and αS and oligomers was by our of fractions of the the specific of the fractions brain that αS and oligomers and that of the fractions of is to the of the cytosols This that a of PUFAs is associated with αS under conditions. an in PUFA levels was also found in the high-speed membrane fraction of the cells. we that membrane fluidity be by αS, and increased membrane fluidity was observed in neuronal cells overexpressing αS, decreased membrane fluidity were found in the brains of mice genetically deleted of αS. These findings us to a in neuronal of is regulated in part by the oligomerization state of αS. in the levels of soluble αS as observed in the and in PD and DLB brains (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar), can to the relative amounts of in PUFA can the levels of soluble αS as we observed in cells to PUFAs (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). αS-PUFA interactions to regulate neuronal PUFA levels as well as the oligomerization state of αS. We that this a in that soluble oligomers of endogenous αS in normal mouse brain and oligomers also in neurons expressing human αS (16.Sharon R. Bar-Joseph I. Frosch M.P. Walsh D.M. Hamilton J.A. Selkoe D.J. Neuron. 2003; 37: 583-595Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, 17.Sharon R. Goldberg M.S. Bar-Josef I. Betensky R.A. Shen J. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. 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