title: Alpha-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast.
abstract: A pathological feature of Parkinson's disease is the presence of Lewy bodies within selectively vulnerable neurons. These are ubiquitinated cytoplasmic inclusions containing alpha-synuclein, an abundant protein normally associated with presynaptic terminals. Point mutations in the alpha-synuclein gene (A30P and A53T), as well as triplication of the wild-type (WT) locus, have been linked to autosomal dominant Parkinson's. How these alterations might contribute to disease progression is unclear. Using the genetically tractable yeast Saccharomyces cerevisiae as a model system, we find that both the WT and the A53T isoforms of alpha-synuclein initially localize to the plasma membrane, to which they are delivered via the classical secretory pathway. In contrast, the A30P mutant protein disperses within the cytoplasm and does not associate with the plasma membrane, and its intracellular distribution is unaffected by mutations in the secretory pathway. When their expression is elevated, WT and A53T, but not A30P, are toxic to cells. At moderate levels of expression, WT and A53T induce the cellular stress (heat-shock) response and are toxic to cells bearing mutations in the 20S proteasome. Our results reveal a link between plasma membrane targeting of alpha-synuclein and its toxicity in yeast and suggest a role for the quality control (QC) system in the cell's effort to deal with this natively unfolded protein.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Science Center, Shreveport, 71130-3932, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Dixon
authors.forename: Neal
authors.initials: N
authors.lastname: Mathias
authors.forename: Richard M
authors.initials: RM
authors.lastname: Zweig
authors.forename: Donnie A
authors.initials: DA
authors.lastname: Davis
authors.forename: David S
authors.initials: DS
authors.lastname: Gross
mesh_terms: D019943:Amino Acid Substitution; D002462:Cell Membrane / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D017930:Genes, Reporter; D006358:Hot Temperature; D009154:Mutation; D010300:Parkinson Disease / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; D046988:Proteasome Endopeptidase Complex
references.citation: Neuroreport. 2002 Aug 7;13(11):1437-41
references.pmid: 12167769
references.citation: J Neurol. 1998 Nov;245(11 Suppl 3):P1-3
references.pmid: 9808333
references.citation: Brain Pathol. 2002 Oct;12(4):499-510
references.pmid: 12408237
references.citation: J Cell Sci. 2002 Dec 15;115(Pt 24):4957-68
references.pmid: 12432082
references.citation: J Biol Chem. 2002 Dec 13;277(50):48984-92
references.pmid: 12351643
references.citation: Eukaryot Cell. 2003 Feb;2(1):123-33
references.pmid: 12582129
references.citation: J Biol Chem. 2003 Mar 7;278(10):7755-64
references.pmid: 12499367
references.citation: J Biol Chem. 2003 Apr 25;278(17):15313-8
references.pmid: 12586824
references.citation: Curr Opin Genet Dev. 2003 Jun;13(3):253-61
references.pmid: 12787787
references.citation: J Mol Biol. 2003 Jun 13;329(4):763-78
references.pmid: 12787676
references.citation: Science. 2003 Oct 31;302(5646):841
references.pmid: 14593171
references.citation: Science. 2003 Dec 5;302(5651):1772-5
references.pmid: 14657500
references.citation: J Biol Chem. 2004 Mar 26;279(13):12924-34
references.pmid: 14711827
references.citation: Biochemistry. 2004 Apr 27;43(16):4810-8
references.pmid: 15096050
references.citation: J Mol Neurosci. 2004;23(1-2):23-34
references.pmid: 15126689
references.citation: Cell. 1980 Aug;21(1):205-15
references.pmid: 6996832
references.citation: J Neurosci. 1988 Aug;8(8):2804-15
references.pmid: 3411354
references.citation: J Cell Biol. 1989 Apr;108(4):1271-81
references.pmid: 2466847
references.citation: J Biol Chem. 1999 May 28;274(22):15937-46
references.pmid: 10336500
references.citation: J Cell Biol. 1999 Jul 12;146(1):125-40
references.pmid: 10402465
references.citation: Biochemistry. 2004 Dec 28;43(51):16233-42
references.pmid: 15610017
references.citation: Hum Mol Genet. 2001 Apr 15;10(9):919-26
references.pmid: 11309365
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1589-94
references.pmid: 10677504
references.citation: Science. 2000 Feb 18;287(5456):1265-9
references.pmid: 10678833
references.citation: J Biol Chem. 2000 Mar 24;275(12):8812-6
references.pmid: 10722726
references.citation: Nature. 2000 Mar 23;404(6776):394-8
references.pmid: 10746727
references.citation: Mol Biol Cell. 2000 Jul;11(7):2335-47
references.pmid: 10888672
references.citation: J Neurosci. 2000 Aug 15;20(16):6021-9
references.pmid: 10934251
references.citation: J Neurosci. 2000 Sep 1;20(17):6365-73
references.pmid: 10964942
references.citation: Cell Mol Life Sci. 2000 Dec;57(13-14):1894-908
references.pmid: 11215516
references.citation: Science. 2001 May 25;292(5521):1552-5
references.pmid: 11375494
references.citation: Neurobiol Dis. 2001 Jun;8(3):535-9
references.pmid: 11442360
references.citation: Science. 2001 Jul 13;293(5528):263-9
references.pmid: 11431533
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13201-6
references.pmid: 11687606
references.citation: Eur J Biochem. 2002 Jan;269(1):148-56
references.pmid: 11784308
references.citation: Acta Neuropathol. 2002 Feb;103(2):145-51
references.pmid: 11810180
references.citation: J Mol Biol. 2002 Jan 25;315(4):799-807
references.pmid: 11812148
references.citation: J Biol Chem. 2002 Feb 22;277(8):6344-52
references.pmid: 11744721
references.citation: Bioessays. 2002 Apr;24(4):308-18
references.pmid: 11948617
references.citation: Science. 2002 Jun 14;296(5575):1991-5
references.pmid: 12065827
references.citation: Mol Cell Biol. 1989 Nov;9(11):4789-98
references.pmid: 2689867
references.citation: EMBO J. 1991 Mar;10(3):555-62
references.pmid: 2001673
references.citation: Biotechniques. 1992 Jul;13(1):18-20
references.pmid: 1503765
references.citation: J Biol Chem. 1993 Mar 5;268(7):5115-20
references.pmid: 8383129
references.citation: Yeast. 1993 Jul;9(7):715-22
references.pmid: 8368005
references.citation: Cell. 1994 Jun 17;77(6):895-907
references.pmid: 8004676
references.citation: Nature. 1994 Jul 21;370(6486):191-3
references.pmid: 8028665
references.citation: Cell. 1994 Oct 21;79(2):245-58
references.pmid: 7954793
references.citation: Nature. 1994 Nov 3;372(6501):55-63
references.pmid: 7969419
references.citation: Neuron. 1995 Aug;15(2):361-72
references.pmid: 7646890
references.citation: J Neuropathol Exp Neurol. 1996 Aug;55(8):889-95
references.pmid: 8759778
references.citation: Biochemistry. 1996 Oct 29;35(43):13709-15
references.pmid: 8901511
references.citation: Mol Cells. 1997 Feb 28;7(1):78-83
references.pmid: 9085269
references.citation: Cell. 1997 May 16;89(4):495-8
references.pmid: 9160741
references.citation: Science. 1997 Jun 27;276(5321):2045-7
references.pmid: 9197268
references.citation: Nature. 1997 Jul 24;388(6640):329, 331
references.pmid: 9237748
references.citation: Nature. 1997 Aug 28;388(6645):839-40
references.pmid: 9278044
references.citation: Nat Genet. 1998 Feb;18(2):106-8
references.pmid: 9462735
references.citation: Nature. 1998 Apr 9;392(6676):605-8
references.pmid: 9560156
references.citation: Ann Neurol. 1998 Sep;44(3 Suppl 1):S72-84
references.pmid: 9749577
references.citation: J Biol Chem. 1998 Oct 9;273(41):26292-4
references.pmid: 9756856
references.citation: J Neurosci. 2002 Oct 15;22(20):8797-807
references.pmid: 12388586