Cytosolic Proteins Regulate α-Synuclein Dissociation from Presynaptic Membranes

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9/25/2020 0:00

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Résumé

Intracellular accumulation of insoluble α-synuclein in Lewy bodies is a key neuropathological trait of Parkinson disease (PD). Neither the normal function of α-synuclein nor the biochemical mechanisms that cause its deposition are understood, although both are likely influenced by the interaction of α-synuclein with vesicular membranes, either for a physiological role in vesicular trafficking or as a pathological seeding mechanism that exacerbates the propensity of α-synuclein to self-assemble into fibrils. In addition to the α-helical form that is peripherally-attached to vesicles, a substantial portion of α-synuclein is freely diffusible in the cytoplasm. The mechanisms controlling α-synuclein exchange between these compartments are unknown and the possibility that chronic dysregulation of membrane-bound and soluble α-synuclein pools may contribute to Lewy body pathology led us to search for cellular factors that can regulate α-synuclein membrane interactions. Here we reveal that dissociation of membrane-bound α-synuclein is dependent on brain-specific cytosolic proteins and insensitive to calcium or metabolic energy. Two PD-linked mutations (A30P and A53T) significantly increase the cytosol-dependent α-synuclein off-rate but have no effect on cytosol-independent dissociation. These results reveal a novel mechanism by which cytosolic brain proteins modulate α-synuclein interactions with intracellular membranes. Importantly, our finding that α-synuclein dissociation is up-regulated by both familial PD mutations implicates cytosolic cofactors in disease pathogenesis and as molecular targets to influence α-synuclein aggregation. Intracellular accumulation of insoluble α-synuclein in Lewy bodies is a key neuropathological trait of Parkinson disease (PD). Neither the normal function of α-synuclein nor the biochemical mechanisms that cause its deposition are understood, although both are likely influenced by the interaction of α-synuclein with vesicular membranes, either for a physiological role in vesicular trafficking or as a pathological seeding mechanism that exacerbates the propensity of α-synuclein to self-assemble into fibrils. In addition to the α-helical form that is peripherally-attached to vesicles, a substantial portion of α-synuclein is freely diffusible in the cytoplasm. The mechanisms controlling α-synuclein exchange between these compartments are unknown and the possibility that chronic dysregulation of membrane-bound and soluble α-synuclein pools may contribute to Lewy body pathology led us to search for cellular factors that can regulate α-synuclein membrane interactions. Here we reveal that dissociation of membrane-bound α-synuclein is dependent on brain-specific cytosolic proteins and insensitive to calcium or metabolic energy. Two PD-linked mutations (A30P and A53T) significantly increase the cytosol-dependent α-synuclein off-rate but have no effect on cytosol-independent dissociation. These results reveal a novel mechanism by which cytosolic brain proteins modulate α-synuclein interactions with intracellular membranes. Importantly, our finding that α-synuclein dissociation is up-regulated by both familial PD mutations implicates cytosolic cofactors in disease pathogenesis and as molecular targets to influence α-synuclein aggregation. Withdrawal: Cytosolic proteins regulate α-synuclein dissociation from presynaptic membranes.Journal of Biological ChemistryVol. 295Issue 39PreviewVOLUME 281 (2006) PAGES 32148–32155 Full-Text PDF Open Access α-Synuclein (α-syn) 3The abbreviations used are: α-syn, α-synuclein; PD, Parkinson disease; Wt, wild-type; ANOVA, analysis of variance; Tg, transgenic; ATPγS, adenosine 5′-O-(thiotriphosphate); GTPγS, guanosine 5′-3-O-(thio)triphosphate; AMP-PNP, adenosine 5′-(β,γ-imino)triphosphate; AMP-CP, α,β-methylene adenosine diphosphate. is a member of a multigene synuclein family that is highly abundant in presynaptic terminals of mammalian brain (1Lavedan C. Genome Res. 1998; 8: 871-880Crossref PubMed Scopus (275) Google Scholar, 2Clayton D.F. George J.M. J. Neurosci. Res. 1999; 58: 120-129Crossref PubMed Scopus (392) Google Scholar). The function of α-syn is poorly resolved, although it is attributed with wide ranging roles in vesicular trafficking and vesicle biogenesis and as a molecular chaperone (3Bennett M.C. Pharmacol. Ther. 2005; 105: 311-331Crossref PubMed Scopus (160) Google Scholar). α-Syn is also implicated in a broad spectrum of neurodegenerative disorders collectively named synucleinopathies, being a primary component of Lewy bodies (4Kruger R. Muller T. Riess O. J. Neural Transm. 2000; 107: 31-40Crossref PubMed Scopus (75) Google Scholar), and as a fragment in Alzheimer disease plaques (5Ueda K. Saitoh T. Mori H. Biochem. Biophys. Res. Commun. 1994; 205: 1366-1372Crossref PubMed Scopus (122) Google Scholar). In a small number of pedigrees, autosomal-dominant inheritance of Parkinson disease (PD) is linked to either multiplication of the normal α-syn gene or to one of three missense mutations (A30P, E46K, and A53T) (6Dawson T.M. Dawson V.L. J. Clin. Invest. 2003; 111: 145-151Crossref PubMed Scopus (209) Google Scholar, 7Zarranz J.J. Alegre J. Gomez-Esteban J.C. Lezcano E. Ros R. Ampuero I. Vidal L. Hoenicka J. Rodriguez O. Atares B. Llorens V. Tortosa E.G. Del Ser T. Munoz D.G. de Yebenes J.G. Ann. Neurol. 2004; 55: 164-173Crossref PubMed Scopus (2244) Google Scholar). In vitro studies suggest that α-syn is natively unfolded in aqueous solution, and exposure to lipids stabilizes the amino terminus in an amphipathic α-helix that aligns polar and non-polar residues into opposing orientations (8Jo E. McLaurin J. Yip C.M. St George-Hyslop P. Fraser P.E. J. Biol. Chem. 2000; 275: 34328-34334Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar, 9Eliezer D. Kutluay E. Bussell Jr., R. Browne G. J. Mol. Biol. 2001; 307: 1061-1073Crossref PubMed Scopus (888) Google Scholar, 10Chandra S. Chen X. Rizo J. Jahn R. Sudhof T.C. J. Biol. Chem. 2003; 278: 15313-15318Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar, 11Jao C.C. Der-Sarkissian A. Chen J. Langen R. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 8331-8336Crossref PubMed Scopus (318) Google Scholar). Presumably, this secondary structure confers the lipid-binding properties for direct membrane interaction such that purified recombinant α-syn can bind to small diameter artificial vesicles rich in acidic phospholipids (8Jo E. McLaurin J. Yip C.M. St George-Hyslop P. Fraser P.E. J. Biol. Chem. 2000; 275: 34328-34334Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar, 12Kubo S. Nemani V.M. Chalkley R.J. Anthony M.D. Hattori N. Mizuno Y. Edwards R.H. Fortin D.L. J. Biol. Chem. 2005; 280: 31664-31672Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar), to purified synaptic vesicles (13Maroteaux L. Scheller R.H. Brain Res. Mol. Brain Res. 1991; 11: 335-343Crossref PubMed Scopus (301) Google Scholar, 14Jensen P.H. Nielsen M.S. Jakes R. Dotti C.G. Goedert M. J. Biol. Chem. 1998; 273: 26292-26294Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar), and to membranes within intact cells (15Fortin D.L. Troyer M.D. Nakamura K. Kubo S. Anthony M.D. Edwards R.H. J. Neurosci. 2004; 24: 6715-6723Crossref PubMed Scopus (430) Google Scholar). Most studies examining α-syn membrane binding have used either artificial phospholipids or purified membranes, without consideration to the potential regulatory function of soluble or membrane factors that may be pertinent to disease progression. Previous investigations were equivocal on whether α-syn mutations (A30P and A53T) affect membrane interactions; the A30P or A53T mutation had little or no effect on α-syn binding (16Perrin R.J. Woods W.S. Clayton D.F. George J.M. J. Biol. Chem. 2000; 275: 34393-34398Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar, 17McLean P.J. Kawamata H. Ribich S. Hyman B.T. J. Biol. Chem. 2000; 275: 8812-8816Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar), the A53T mutation reduced (8Jo E. McLaurin J. Yip C.M. St George-Hyslop P. Fraser P.E. J. Biol. Chem. 2000; 275: 34328-34334Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar) or increased (18Sharon 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 (272) Google Scholar, 19Lotharius J. Barg S. Wiekop P. Lundberg C. Raymon H.K. Brundin P. J. Biol. Chem. 2002; 277: 38884-38894Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar) the membrane binding, or the A30P had reduced binding to purified synaptic vesicles (14Jensen P.H. Nielsen M.S. Jakes R. Dotti C.G. Goedert M. J. Biol. Chem. 1998; 273: 26292-26294Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, 20Iwai A. Masliah E. Yoshimoto M. Ge N. Flanagan L. de Silva H.A. Kittel A. Saitoh T. Neuron. 1995; 14: 467-475Abstract Full Text PDF PubMed Scopus (1153) Google Scholar, 21Jo E. Fuller N. Rand R.P. George-Hyslop P. Fraser P.E. J. Mol. Biol. 2002; 315: 799-807Crossref PubMed Scopus (197) Google Scholar). Further complexity may also arise from reversible membrane interaction, akin to that of cytosolic regulators of vesicular trafficking whose direct or indirect association with vesicle membranes is necessarily transient (e.g. exocytosis: NSF, α/β-SNAP, rab3, rabphilin, synapsin, CAPS; endocytosis: clathrin/adaptor, dynamin) (22Lin R.C. Scheller R.H. Annu. Rev. Cell Dev. Biol. 2000; 16: 19-49Crossref PubMed Scopus (424) Google Scholar, 23Slepnev V.I. De Camilli P. Nat. Rev. Neurosci. 2000; 1: 161-172Crossref PubMed Scopus (427) Google Scholar, 24Sudhof T.C. Annu. Rev. Neurosci. 2004; 27: 509-547Crossref PubMed Scopus (1919) Google Scholar). Association and dissociation is coupled to the vesicle life cycle, dictated by cation fluxes, nucleotide triphosphate cleavage, and post-translational modifications. In the case of rab3, an additional mechanism governs its membrane attachment. Another cytosolic protein, GDP-dissociation inhibitor, is essential to extract rab3 off exocytosing vesicles and deliver it to newly synthesized vesicles (25Araki S. Kikuchi A. Hata Y. Isomura M. Takai Y. J. Biol. Chem. 1990; 265: 13007-13015Abstract Full Text PDF PubMed Google Scholar, 26Fischer von Mollard G. Sudhof T.C. Jahn R. Nature. 1991; 349: 79-81Crossref PubMed Scopus (343) Google Scholar, 27Wu S.K. Zeng K. Wilson I.A. Balch W.E. Trends Biochem. Sci. 1996; 21: 472-476Abstract Full Text PDF PubMed Scopus (88) Google Scholar). It is unknown whether α-synuclein exchange occurs between soluble and membrane compartments or even whether α-syn can dissociate from reconstituted or biological membranes. The possibility that chronic dysregulation of subcellular α-synuclein pools may contribute to PD and other synucleinopathies prompted our search for cellular factors that affect α-synuclein membrane interactions. To address this, we developed an assay comprised of permeabilized synaptosomes and report here that α-syn dissociation from presynaptic membranes requires cytosolic proteins from the brain. Particularly relevant to disease pathogenesis was the finding that cytosol-dependent α-syn dissociation was significantly increased by two PD-related mutations (A30P and A53T) suggesting a mechanism whereby cytosolic cofactors can regulate α-syn solubility and, thereby, modulate disease progression. Transgene Construction and Generation of Transgenic Mice—The human α-syn gene containing a eukaryotic Kozak initiation sequence (GCCGCCACC) (28Kozak M. Nucleic Acids Res. 1984; 12: 857-872Crossref PubMed Scopus (2623) Google Scholar, 29Kozak M. J. Cell Biol. 1991; 115: 887-903Crossref PubMed Scopus (1475) Google Scholar) upstream of the start codon was ligated into a linearized cos-Tet expression vector containing the Syrian hamster prion protein promoter gene (30Scott M.R. Kohler R. Foster D. Prusiner S.B. Protein Sci. 1992; 1: 986-997Crossref PubMed Scopus (222) Google Scholar, 31Citron M. Westaway D. Xia W. Carlson G. Diehl T. Levesque G. Johnson-Wood K. Lee M. Seubert P. Davis A. Kholodenko D. Motter R. Sherrington R. Perry B. Yao H. Strome R. Lieberburg I. Rommens J. Kim S. Schenk D. Fraser P. St George H.P. Selkoe D.J. Nat. Med. 1997; 3: 67-72Crossref PubMed Scopus (1176) Google Scholar). A30P and A53T α-syn mutant transgenes were generated using the Quick change kit (Stratagene). Following microinjection into fertilized oocytes of FVB/N mice, positive founders were identified by amplification of genomic DNA and bred to FVB wild-type mice. To generate α-syn Tg mice lacking endogenous murine α-syn, the α-syn Tg mice were crossed with mice positive for α-syn were and were for the of the gene and the of the endogenous α-syn gene as A. Y. I. D. P.E. N. J.M. M. A. M. H. D. A. Neuron. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). were to in the for the and of were as von Mollard G. Sudhof T.C. Jahn R. Nature. 1991; 349: 79-81Crossref PubMed Scopus (343) Google Scholar, A. S. A. Balch W.E. Neuron. 1998; 21: Full Text Full Text PDF PubMed Scopus Google Scholar). from mice (A30P, and were and with in and and for The was for and the in A. The was a and in and for The containing intact was in and and for The was by two in for and in and for synaptosomes were in and in with or without α-syn brain or membrane and by for The was to such as membranes or synaptic vesicles soluble α-syn by from α-Syn and were in of The was for and the was for The was with for for and Protein was by protein assay were in and and by using were to and by α-syn and our to a or or were by using and with a and were with using for between two or for Cytosolic α-Syn from regulators of α-syn we the of cytosolic proteins on the interaction of α-syn with membranes. α-syn dissociation from membranes from of mice human α-syn as the of membrane-bound α-syn in the or of brain from mice as the soluble synaptosomes from α-syn brain in of α-syn which the soluble The α-syn is with the membrane in and is to membrane by The of α-syn into the was increased by the addition of membrane such as were by the membrane of membranes with to α-syn α-syn in to or of which had effect The to dissociate from presynaptic membranes was to human α-syn, endogenous α-syn from mice also cytosol-dependent dissociation from presynaptic membranes cytosol-dependent α-syn dissociation from membranes. α-Syn Tg membranes and brain were to the role of cytosolic proteins on α-syn dissociation. for of membranes of membrane with protein increased soluble human α-syn, as by The membrane protein was into the but with the membrane with of on dissociation of human α-syn and of and to α-syn by α-Syn dissociation in the of was by of membranes with α-syn with without but or dissociation of murine with endogenous murine α-syn from mice also cytosol-dependent dissociation from membranes for with of a protein, affect α-syn solubility the cytosolic was and as or with to α-syn suggesting that this requires cytosolic proteins To that was by exposure to membranes, we that of with an of α-syn dissociation of were significantly with brain suggesting that the factors are The cytosol-dependent component of α-syn dissociation from synaptic membranes was to from to In cytosol-independent α-syn dissociation was insensitive this Cytosolic for α-Syn of α-syn dissociation from membranes are in the and the of α-syn dissociation were increased by the The of soluble α-syn a within suggesting that cytosolic factors are the of our the α-syn of the α-syn, the of the α-syn is we whether of the α-syn was to dissociation by exposure to that additional membrane-bound α-syn be although the in with a in the of was the no additional α-syn was that dissociation requires cytosolic factors and that α-syn is for dissociation by the exposure to whether used one to extract additional α-syn from synaptic membranes. To between α-syn the and we used synaptosomes from mice in the and the dissociation of endogenous murine α-syn using the The containing murine α-syn, was with permeabilized synaptosomes from human α-syn Tg mice that are murine The which is for the human reveal human α-syn from membranes in the of used but using These results suggest that the of cytosolic proteins the of α-syn dissociation and that our α-Syn by or by are to by and the of metabolic we whether α-syn is by in these on α-syn dissociation were in the or of and in the of of suggesting a mechanism we the of and and metabolic in our to α-syn dissociation in the of of these suggesting that α-syn dissociation occurs of Parkinson α-Syn whether the A30P and affect α-syn dissociation using of membrane of membrane as with α-syn, exposure also increased the dissociation of mutant α-syn from synaptic membranes. the dissociation of both A30P and A53T which was was significantly that of α-syn the To the possibility that in dissociation of α-syn are to in expression or subcellular we the of α-syn in α-syn expression in the cytosolic by to the α-syn by of the of α-syn in terminals is soluble the expression of and mutant human α-syn were The which the α-syn in our dissociation were and α-syn in the were no between the membrane of and α-syn In this that the mutations the α-syn interaction with association was with the of α-syn from membranes is a that is by the two missense of and synuclein is by PD α-Syn expression and in were between synaptosomes from A30P and A53T α-syn Tg mice. α-syn, and in the of intact synaptosomes into and and or and of the cytosolic from and and from and were between and mutant α-syn expression ANOVA, cytosolic membrane α-syn was between of the synaptosomes from and no were in the of membrane α-syn in synaptosomes from α-syn and mutant Tg mice ANOVA, of α-syn interaction that the portion into an that into membrane (8Jo E. McLaurin J. Yip C.M. St George-Hyslop P. Fraser P.E. J. Biol. Chem. 2000; 275: 34328-34334Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar, 10Chandra S. Chen X. Rizo J. Jahn R. Sudhof T.C. J. Biol. Chem. 2003; 278: 15313-15318Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar, 11Jao C.C. Der-Sarkissian A. Chen J. Langen R. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 8331-8336Crossref PubMed Scopus (318) Google Scholar, R.J. Woods W.S. Clayton D.F. George J.M. J. Biol. Chem. 2000; 275: 34393-34398Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar, M. J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). In with this our results that the of α-syn is with membranes in although substantial portion is freely diffusible within the cytoplasm. these and diffusible pools are and whether exchange occurs between these α-syn compartments is we that α-syn with the membrane can be into the soluble in the of brain was to a of membrane with the membrane and the was by to the had no affect on α-syn in the of the likely of cytosolic factors to membrane of brain with or the a role for cytosolic proteins in controlling α-syn The factors to be in brain of was to α-syn dissociation as brain The proteins α-syn dissociation are in in and are the of our exposure to membranes was to cytosolic to extract membrane α-syn that with membranes no additional soluble In presynaptic membranes α-syn, which be with of this that the and of α-syn dissociation is dependent on the of cytosolic additional studies be to whether of the α-syn that membrane-bound is from the The cytosolic proteins in our are presynaptic in as a of with and from cells in brain. the portion of α-syn that can be from membranes is likely to be in intact cells the we is with a report by Fortin D.L. Nemani V.M. Anthony M.D. Edwards R.H. J. Neurosci. 2005; PubMed Scopus Google Scholar) that α-syn in primary synaptic and that the as α-syn substantial and can be from in the of the α-syn from in a suggesting that α-syn and that is an also or a direct for nucleotide triphosphate in α-syn dissociation. it is likely that regulatory are in our our α-syn dissociation may the of or with D.L. Nemani V.M. Anthony M.D. Edwards R.H. J. Neurosci. 2005; PubMed Scopus Google Scholar). results suggest a of α-syn interaction with membranes, in which cytosolic proteins the exchange of α-syn with a diffusible and may in studies the of soluble and α-syn, which from M.C. Kim M. George J.M. Clayton D.F. Hyman B.T. J. Neurol. 1996; 55: PubMed Scopus Google Scholar, P.J. M. L. Muller V. S. N. H. T. H. K. N. P. H.A. C. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) to soluble (13Maroteaux L. Scheller R.H. Brain Res. Mol. Brain Res. 1991; 11: 335-343Crossref PubMed Scopus (301) Google Scholar). The that of the α-syn in synaptosomes is membrane-bound that dissociation is by physiological and that the between membrane and soluble pools is by to membranes. The cytosolic that α-syn dissociation between the α-syn and the A30P and A53T mutations the α-syn off-rate but had no effect on the cytosol-independent dissociation. was although (16Perrin R.J. Woods W.S. Clayton D.F. George J.M. J. Biol. Chem. 2000; 275: 34393-34398Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar), have that the A30P mutation A53T) binding S. Nemani V.M. Chalkley R.J. Anthony M.D. Hattori N. Mizuno Y. Edwards R.H. Fortin D.L. J. Biol. Chem. 2005; 280: 31664-31672Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 14Jensen P.H. Nielsen M.S. Jakes R. Dotti C.G. Goedert M. J. Biol. Chem. 1998; 273: 26292-26294Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, 21Jo E. Fuller N. Rand R.P. George-Hyslop P. Fraser P.E. J. Mol. Biol. 2002; 315: 799-807Crossref PubMed Scopus (197) Google Scholar, R. D. 2004; PubMed Scopus Google Scholar). studies the of purified recombinant α-syn to into purified or artificial lipids and for cofactors or we in or mutant α-syn expression in our mice or between soluble and membrane in with studies on intact no effect on membrane interaction by the A30P mutation P.J. Kawamata H. Ribich S. Hyman B.T. J. Biol. Chem. 2000; 275: 8812-8816Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar) and with other the of soluble and α-syn P.J. M. L. Muller V. H. A. M. U. P.H. A. E. H.A. C. J. Neurosci. 2000; PubMed Google Scholar) nor its W. W. D.L. Lee J. 2004; PubMed Scopus Google Scholar) is by the A30P in our which biological membranes and potential endogenous factors that in α-syn membrane A53T α-syn was as likely to dissociate in the of as A30P α-syn, suggesting that the mutations may a effect that is purified are used to α-syn membrane assay on as the in to the that be by the of presynaptic α-syn that is freely diffusible in cytoplasm. we address whether other presynaptic proteins are also into the cytosolic with α-syn, this is a likely presynaptic proteins are with the membrane and a mechanism that its direct or indirect membrane interaction (22Lin R.C. Scheller R.H. Annu. Rev. Cell Dev. Biol. 2000; 16: 19-49Crossref PubMed Scopus (424) Google Scholar, 23Slepnev V.I. De Camilli P. Nat. Rev. Neurosci. 2000; 1: 161-172Crossref PubMed Scopus (427) Google Scholar, 24Sudhof T.C. Annu. Rev. Neurosci. 2004; 27: 509-547Crossref PubMed Scopus (1919) Google Scholar). These are by either a membrane protein (e.g. (e.g. (e.g. and nucleotide triphosphate (e.g. NSF, In are between the dissociation of α-syn and the of rab3, a protein that dissociation and association from vesicles with the of GDP-dissociation (25Araki S. Kikuchi A. Hata Y. Isomura M. Takai Y. J. Biol. Chem. 1990; 265: 13007-13015Abstract Full Text PDF PubMed Google Scholar, 26Fischer von Mollard G. Sudhof T.C. Jahn R. Nature. 1991; 349: 79-81Crossref PubMed Scopus (343) Google Scholar, 27Wu S.K. Zeng K. Wilson I.A. Balch W.E. Trends Biochem. Sci. 1996; 21: 472-476Abstract Full Text PDF PubMed Scopus (88) Google Scholar). a and its is by its terminus that into A. K. Cell Mol. Sci. 2005; PubMed Scopus Google Scholar). GDP-dissociation likely the from aqueous of from membranes. In the case of α-syn, its is to into an amphipathic α-helix that of residues into the C.C. Der-Sarkissian A. Chen J. Langen R. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 8331-8336Crossref PubMed Scopus (318) Google Scholar). dissociation from membranes either of the α-helix or of mechanisms are with a for a cytosolic that α-syn the effect by both PD-linked α-syn mutations to α-syn in the of implicates the as cytosolic in the here to α-syn membrane interactions can be used to and the cytosolic that α-syn into and exchange between Importantly, the mechanism may be to as a of α-syn solubility in as to its

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Revue

Journal of Biological Chemistry

Thématique

Parkinson's Disease Mechanisms and Treatments

Domaine

Medicine

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Occupational Cancer Research CentreUniversity of Toronto

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Mots-clés

CytosolAlpha-synucleinIntracellularCell biologyLewy bodyCytoplasmBiologySynucleinChemistryBiochemistryParkinson's diseaseDiseasePathologyMedicine

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