title: A powerful yeast model to investigate the synergistic interaction of α-synuclein and tau in neurodegeneration.
abstract: Several studies revealed consistent overlap between synucleinopathies and tauopathies, demonstrating that α-synuclein (ASYN) and tau co-localize in neurofibrillary tangles and in Lewy bodies from Alzheimer's and Parkinson's disease patients and corresponding animal models. Additionally, it has been shown that ASYN can act as an initiator of tau aggregation and phosphorylation and that these two proteins directly interact. Despite these evidences, the cellular pathway implicated in this synergistic interaction remains to be clarified. The aim of this study was to create a yeast model where the concomitant expression of ASYN and tau can be used to perform genome wide screenings for the identification of genes that modulate this interaction, in order to shed light into the pathological mechanism of cell dysfunction and to provide new targets for future therapeutic intervention. We started by validating the synergistic toxicity of tau and ASYN co-expression in yeast, by developing episomal and integrative strains expressing WT and mutant forms of both proteins, alone or in combination. The episomal strains showed no differences in growth delay upon expression of ASYN isoforms (WT or A53T) alone or in combination with tau 2N/4R isoforms (WT or P301L). However, in these strains, the presence of ASYN led to increased tau insolubility and correlated with increased tau phosphorylation in S396/404, which is mainly mediated by RIM11, the human homolog of GSK3β in yeast. On the other hand, the integrative strains showed a strong synergistic toxic effect upon co-expression of ASYN WT and tau WT, which was related to high levels of intracellular ASYN inclusions and increased tau phosphorylation and aggregation. Taken together, the strains described in the present study are able to mimic relevant pathogenic features involved in neurodegeneration and are powerful tools to identify potential target genes able to modulate the synergistic pathway driven by ASYN and tau interaction.
authors: BIOALVO, Serviços Investigação e Desenvolvimento em Biotecnologia S.A., Edificio ICAT, Campus da FCUL, Campo Grande, Lisboa, Portugal.
authors: Gianmario
authors: G
authors: Ciaccioli
authors: Ana
authors: A
authors: Martins
authors: Cátia
authors: C
authors: Rodrigues
authors: Helena
authors: H
authors: Vieira
authors: Patrícia
authors: P
authors: Calado
mesh_terms: D019636:Neurodegenerative Diseases / Q000378:metabolism*; D011485:Protein Binding; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D016875:tau Proteins
references: Exp Neurol. 2010 Sep;225(1):210-8
references: 20599975
references: J Neurosci. 2011 Jan 12;31(2):700-11
references: 21228179
references: FEBS J. 2011 Dec;278(24):4895-904
references: 21985244
references: J Cell Biol. 1996 Jul;134(2):413-27
references: 8707826
references: Cell Death Differ. 2010 May;17(5):746-53
references: 20019751
references: Biochim Biophys Acta. 2006 Mar;1762(3):312-8
references: 16413174
references: J Biol Chem. 2003 Aug 15;278(33):30896-904
references: 12743123
references: Parkinsonism Relat Disord. 2012 Mar;18(3):257-62
references: 22104010
references: J Neuropathol Exp Neurol. 2008 Nov;67(11):1084-96
references: 18957893
references: Exp Neurol. 2005 Apr;192(2):274-87
references: 15755545
references: Science. 1997 Jun 27;276(5321):2045-7
references: 9197268
references: Science. 2003 Dec 5;302(5651):1772-5
references: 14657500
references: Science. 2003 Oct 31;302(5646):841
references: 14593171
references: Arch Neurol. 2004 Dec;61(12):1915-9
references: 15596612
references: FASEB J. 2006 Nov;20(13):2302-12
references: 17077307
references: Mov Disord. 2003 Sep;18 Suppl 6:S21-7
references: 14502652
references: Anal Biochem. 1976 May 7;72:248-54
references: 942051
references: Curr Drug Targets. 2006 Nov;7(11):1455-65
references: 17100585
references: PLoS One. 2011 Mar 21;6(3):e17953
references: 21445308
references: Brain Res Mol Brain Res. 1996 Jul;39(1-2):79-88
references: 8804716
references: J Geriatr Psychiatry Neurol. 2010 Dec;23(4):228-42
references: 20938043
references: Nat Genet. 1998 Feb;18(2):106-8
references: 9462735
references: Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9
references: 15451224
references: J Mol Biol. 2005 Sep 2;351(5):1081-100
references: 16051265
references: Neuroscience. 2008 Apr 9;152(4):913-23
references: 18343584
references: Trends Mol Med. 2009 Mar;15(3):112-9
references: 19246243
references: Acta Neuropathol. 2003 Nov;106(5):419-35
references: 12955398
references: Nature. 1997 Aug 28;388(6645):839-40
references: 9278044
references: Am J Pathol. 2011 Feb;178(2):803-16
references: 21281813
references: J Biol Chem. 1999 Sep 3;274(36):25481-9
references: 10464279
references: Int J Biochem Cell Biol. 2010 Nov;42(11):1775-8
references: 20678581
references: Exp Cell Res. 2005 Aug 1;308(1):78-84
references: 15904919
references: FEMS Yeast Res. 2010 Dec;10(8):992-1005
references: 20662935
references: Nat Genet. 2007 Apr;39(4):550-4
references: 17322879
references: J Biol Chem. 2010 Dec 3;285(49):38692-9
references: 20921222
references: J Biol Chem. 2002 Nov 15;277(46):44576-81
references: 12226100
references: Neurobiol Dis. 2007 Jun;26(3):521-31
references: 17408955
references: Ann Neurol. 2004 Feb;55(2):164-73
references: 14755719
references: J Neurosci. 2005 Jun 1;25(22):5446-54
references: 15930395
references: Acta Neuropathol. 2000 May;99(5):469-81
references: 10805089
references: J Biol Chem. 2006 Sep 1;281(35):25388-97
references: 16818492
references: Am J Pathol. 2006 May;168(5):1598-607
references: 16651626
references: J Bacteriol. 1983 Jan;153(1):163-8
references: 6336730
references: J Neurosci. 2011 May 25;31(21):7604-18
references: 21613474
references: Cell Struct Funct. 2003 Jun;28(3):187-93
references: 12951439
references: Biochim Biophys Acta. 2000 Jul 26;1502(1):110-21
references: 10899436
references: Brain Res. 1989 Jan 16;477(1-2):90-9
references: 2495152
references: Curr Treat Options Neurol. 2012 Apr;14(2):126-36
references: 22307450
references: Proc Natl Acad Sci U S A. 1986 Jun;83(11):4044-8
references: 2424016
references: J Mol Neurosci. 2006;28(2):161-78
references: 16679556
references: Am J Pathol. 1999 Dec;155(6):2153-65
references: 10595944
references: Science. 2003 Apr 25;300(5619):636-40
references: 12714745
references: Ann Neurol. 2011 May;69(5):778-92
references: 21391235
references: Indian J Cancer. 2004 Jan-Mar;41(1):47
references: 15105580
references: Parkinsonism Relat Disord. 2006 Oct;12(7):399-409
references: 16797215
references: PLoS One. 2011;6(10):e26609
references: 22039514
references: FEBS J. 2005 Mar;272(6):1386-400
references: 15752356
references: PLoS One. 2011;6(12):e29257
references: 22206005
references: J Alzheimers Dis. 2007 Dec;12(4):365-75
references: 18198423
references: J Neurol Neurosurg Psychiatry. 1995 Feb;58(2):160-6
references: 7876845
references: Science. 2007 May 4;316(5825):750-4
references: 17478722
references: J Biol Chem. 1986 May 5;261(13):6084-9
references: 3084478
references: Cell. 2010 Aug 6;142(3):387-97
references: 20655099
references: J Neurosci. 2010 Sep 29;30(39):13138-49
references: 20881132
references: Science. 2001 Jul 27;293(5530):711-4
references: 11408621
references: Genetics. 2005 May;170(1):47-59
references: 15744056
references: Acta Neuropathol. 2009 Feb;117(2):151-8
references: 19039597
references: Acta Neuropathol. 2006 Feb;111(2):101-8
references: 16482476
references: Int J Alzheimers Dis. 2011 Apr 06;2011:428970
references: 21559193
references: Front Mol Neurosci. 2011 Aug 26;4:17
references: 21904524
references: Protein Cell. 2011 Feb;2(2):141-9
references: 21327870
references: Cold Spring Harb Perspect Med. 2012 Feb;2(2):a009399
references: 22355802
references: Neuromolecular Med. 2003;4(1-2):49-58
references: 14528052
references: J Cell Mol Med. 2011 Aug;15(8):1621-35
references: 21348938