Home LiteratureArticle Details
PMID: 20038714 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models.

Disease models & mechanisms ·Vol. 3 ·No. 3-4 ·2010-00-00 ·Pages 194-208

Su LJ, Auluck PK, Outeiro TF, Yeger-Lotem E, Kritzer JA, Tardiff DF, Strathearn KE, Liu F, Cao S, Hamamichi S, Hill KJ, Caldwell KA, Bell GW, Fraenkel E, Cooper AA, Caldwell GA, McCaffery JM, Rochet JC, Lindquist S

Abstract

alpha-Synuclein (alpha-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression. We also uncovered a core group of proteins with diverse activities related to alpha-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of alpha-syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress alpha-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of alpha-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced alpha-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of alpha-syn foci, re-established ER-to-Golgi trafficking and ameliorated alpha-syn-mediated damage to mitochondria. They also corrected the toxicity of alpha-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of alpha-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.

MeSH Terms
Animals Antiparkinson Agents/pharmacology,therapeutic use Caenorhabditis elegans/drug effects,metabolism Disease Models, Animal Dopamine/metabolism Drug Evaluation, Preclinical Endoplasmic Reticulum/drug effects,metabolism,ultrastructure Gene Expression Profiling Golgi Apparatus/drug effects,metabolism,ultrastructure Mitochondria/drug effects,pathology,ultrastructure Neurons/drug effects,pathology Parkinson Disease/drug therapy,metabolism Protein Transport/drug effects Rats Reactive Oxygen Species/metabolism Rotenone/toxicity Saccharomyces cerevisiae/drug effects Stress, Physiological/drug effects Structure-Activity Relationship alpha-Synuclein/toxicity
Chemicals
Antiparkinson Agents Reactive Oxygen Species alpha-Synuclein Rotenone Dopamine
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Su Linhui Julie
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Auluck Pavan K
Outeiro Tiago Fleming
Yeger-Lotem Esti
Kritzer Joshua A
Tardiff Daniel F
Strathearn Katherine E
Liu Fang
Cao Songsong
Hamamichi Shusei
Hill Kathryn J
Caldwell Kim A
Bell George W
Fraenkel Ernest
Cooper Antony A
Caldwell Guy A
McCaffery J Michael
Rochet Jean-Christophe
Lindquist Susan
References (68)
68 references, click to expand
  1. Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models.
    Nat Chem Biol. 2009 Sep;5(9):655-63 PMID: 19597508
  2. SNCA variants are associated with increased risk for multiple system atrophy.
    Ann Neurol. 2009 May;65(5):610-4 PMID: 19475667
  3. Stress tolerance: the key to effective strains of industrial baker's yeast.
    Nat Biotechnol. 1997 Dec;15(13):1351-7 PMID: 9415886
  4. Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity.
    Hum Mol Genet. 2005 Dec 15;14(24):3801-11 PMID: 16239241
  5. Isolation of yeast mitochondria.
    Methods Mol Biol. 2006;313:33-9 PMID: 16118422
  6. Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults.
    Free Radic Biol Med. 2008 Aug 1;45(3):242-55 PMID: 18456002
  7. Chronic Parkinsonism secondary to intravenous injection of meperidine analogues.
    Psychiatry Res. 1979 Dec;1(3):249-54 PMID: 298352
  8. Regulation of mitochondrial biogenesis in Saccharomyces cerevisiae. Intricate interplay between general and specific transcription factors in the promoter of the QCR8 gene.
    Eur J Biochem. 1995 Oct 1;233(1):200-8 PMID: 7588747
  9. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies.
    Neurosci Lett. 1998 Jul 31;251(3):205-8 PMID: 9726379
  10. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain.
    J Biol Chem. 2008 Apr 4;283(14):9089-100 PMID: 18245082
  11. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria.
    Cell. 1997 Nov 28;91(5):627-37 PMID: 9393856
  12. Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration.
    Neurotoxicology. 2004 Sep;25(5):761-9 PMID: 15288507
  13. Mitofusin 2 tethers endoplasmic reticulum to mitochondria.
    Nature. 2008 Dec 4;456(7222):605-10 PMID: 19052620
  14. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.
    Science. 1997 Jun 27;276(5321):2045-7 PMID: 9197268
  15. Yeast cells provide insight into alpha-synuclein biology and pathobiology.
    Science. 2003 Dec 5;302(5651):1772-5 PMID: 14657500
  16. Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP.
    Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14524-9 PMID: 12376616
  17. Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death.
    J Neurosci. 2006 Jan 4;26(1):41-50 PMID: 16399671
  18. Retrograde signaling is regulated by the dynamic interaction between Rtg2p and Mks1p.
    Mol Cell. 2003 Aug;12(2):401-11 PMID: 14536080
  19. alpha-Synuclein locus triplication causes Parkinson's disease.
    Science. 2003 Oct 31;302(5646):841 PMID: 14593171
  20. Genetic association between alpha-synuclein and idiopathic Parkinson's disease.
    Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5;147B(7):1222-30 PMID: 18404644
  21. Mice lacking alpha-synuclein are resistant to mitochondrial toxins.
    Neurobiol Dis. 2006 Mar;21(3):541-8 PMID: 16298531
  22. Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity.
    Nat Genet. 2009 Mar;41(3):316-23 PMID: 19234470
  23. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.
    Nat Genet. 1998 Feb;18(2):106-8 PMID: 9462735
  24. Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP.
    Exp Neurol. 2004 Apr;186(2):158-72 PMID: 15026254
  25. The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis.
    Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):145-50 PMID: 18162536
  26. A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases.
    J Cell Sci. 2007 May 15;120(Pt 10):1707-16 PMID: 17502481
  27. Flanking sequences profoundly alter polyglutamine toxicity in yeast.
    Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):11045-50 PMID: 16832050
  28. Expanding insights of mitochondrial dysfunction in Parkinson's disease.
    Nat Rev Neurosci. 2006 Mar;7(3):207-19 PMID: 16495942
  29. Alpha-synuclein in Lewy bodies.
    Nature. 1997 Aug 28;388(6645):839-40 PMID: 9278044
  30. Detection of compounds that rescue Rab1-synuclein toxicity.
    Methods Enzymol. 2008;439:339-51 PMID: 18374176
  31. In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies.
    Exp Neurol. 2000 Dec;166(2):324-33 PMID: 11085897
  32. Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans.
    J Neurosci. 2005 Apr 13;25(15):3801-12 PMID: 15829632
  33. Staging of brain pathology related to sporadic Parkinson's disease.
    Neurobiol Aging. 2003 Mar-Apr;24(2):197-211 PMID: 12498954
  34. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system.
    Neuron. 2000 Jan;25(1):239-52 PMID: 10707987
  35. Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications.
    J Biol Chem. 2003 Jul 18;278(29):27230-40 PMID: 12857790
  36. alpha-Synuclein gene haplotypes are associated with Parkinson's disease.
    Hum Mol Genet. 2001 Aug 15;10(17):1847-51 PMID: 11532993
  37. Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage.
    Hum Mol Genet. 2007 Oct 15;16(20):2377-93 PMID: 17412759
  38. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models.
    Science. 2006 Jul 21;313(5785):324-8 PMID: 16794039
  39. Gene Ontology annotations at SGD: new data sources and annotation methods.
    Nucleic Acids Res. 2008 Jan;36(Database issue):D577-81 PMID: 17982175
  40. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein.
    J Neurosci. 2002 Oct 15;22(20):8797-807 PMID: 12388586
  41. Mechanisms of DJ-1 neuroprotection in a cellular model of Parkinson's disease.
    J Neurochem. 2008 Jun 1;105(6):2435-53 PMID: 18331584
  42. Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms.
    Arch Neurol. 2009 Jan;66(1):102-8 PMID: 19139307
  43. Parkinson patient fibroblasts show increased alpha-synuclein expression.
    Exp Neurol. 2008 Aug;212(2):307-13 PMID: 18511044
  44. A rapid and simple method for preparation of RNA from Saccharomyces cerevisiae.
    Nucleic Acids Res. 1990 May 25;18(10):3091-2 PMID: 2190191
  45. Mitochondrial association of alpha-synuclein causes oxidative stress.
    Cell Mol Life Sci. 2008 Apr;65(7-8):1272-84 PMID: 18322646
  46. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons.
    J Neurosci. 2000 May 1;20(9):3214-20 PMID: 10777786
  47. Alpha-synuclein alters proteasome function, protein synthesis, and stationary phase viability.
    J Biol Chem. 2005 Aug 26;280(34):30009-17 PMID: 15941712
  48. The GOA database in 2009--an integrated Gene Ontology Annotation resource.
    Nucleic Acids Res. 2009 Jan;37(Database issue):D396-403 PMID: 18957448
  49. alpha-Synuclein membrane interactions and lipid specificity.
    J Biol Chem. 2000 Nov 3;275(44):34328-34 PMID: 10915790
  50. Alpha-synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae.
    Mol Biol Cell. 2008 Mar;19(3):1093-103 PMID: 18172022
  51. alpha-Synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress.
    J Mol Neurosci. 2006;28(2):161-78 PMID: 16679556
  52. Genomic expression programs in the response of yeast cells to environmental changes.
    Mol Biol Cell. 2000 Dec;11(12):4241-57 PMID: 11102521
  53. Fusion of GAL4-VP16 to a steroid-binding domain provides a tool for gratuitous induction of galactose-responsive genes in yeast.
    Gene. 1993 Sep 6;131(1):129-34 PMID: 8370533
  54. Influence of neurotoxins and oxidative stress on the onset and progression of Parkinson's disease.
    J Neurol. 2000 Apr;247 Suppl 2:II82-94 PMID: 10991671
  55. Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation.
    Exp Neurol. 2003 Jan;179(1):9-16 PMID: 12504863
  56. Mitochondrial dynamics in Parkinson's disease.
    Exp Neurol. 2009 Aug;218(2):247-56 PMID: 19332061
  57. An ER-mitochondria tethering complex revealed by a synthetic biology screen.
    Science. 2009 Jul 24;325(5939):477-81 PMID: 19556461
  58. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis.
    Science. 1983 Feb 25;219(4587):979-80 PMID: 6823561
  59. Import of lipids into mitochondria.
    Prog Lipid Res. 1997 Sep;36(2-3):103-30 PMID: 9624424
  60. Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein.
    Mol Cell Biol. 2005 Nov;25(22):10190-201 PMID: 16260631
  61. Mitochondrial translocation of alpha-synuclein is promoted by intracellular acidification.
    Exp Cell Res. 2008 Jun 10;314(10):2076-89 PMID: 18440504
  62. Pesticide exposure exacerbates alpha-synucleinopathy in an A53T transgenic mouse model.
    Am J Pathol. 2007 Feb;170(2):658-66 PMID: 17255333
  63. Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein.
    J Biol Chem. 2002 Feb 22;277(8):6344-52 PMID: 11744721
  64. alpha-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons.
    J Biol Chem. 2004 Nov 5;279(45):46915-20 PMID: 15322100
  65. Mitochondrial toxins and neurodegenerative diseases.
    Front Biosci. 2007 Jan 01;12:986-1007 PMID: 17127354
  66. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity.
    Nat Genet. 2009 Mar;41(3):308-15 PMID: 19182805
  67. Chronic systemic pesticide exposure reproduces features of Parkinson's disease.
    Nat Neurosci. 2000 Dec;3(12):1301-6 PMID: 11100151
  68. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons.
    Neuron. 2009 Apr 30;62(2):218-29 PMID: 19409267
Article Info
Journal
Disease models & mechanisms
Abbr.
Dis Model Mech
ISSN
1754-8411
DOI
10.1242/dmm.004267
Published
2010-00-00
Epub
2009-00-28
Pages
194-208
Language
English
Region
England
NLM ID
101483332
PMCID
PMC2869493
Subset
IM
Grants
NIGMS NIH HHS · R01 GM089903 · United States
Howard Hughes Medical Institute · United States
NINDS NIH HHS · NS049221 · United States
NINDS NIH HHS · P50 NS038372 · United States
NINDS NIH HHS · R01 NS049221 · United States
Databases
GEO
GSE11633
Corrections
CommentIn
PMID: 20483997
External Links
PubMed source DOI: 10.1242/dmm.004267 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2