MODELING OF MOLECULAR PROCESSES UNDERLYING PARKINSON’S DISEASE IN CELLS OF METHYLOTROPHIC YEAST HANSENULA POLYMORPHA
DOI: http://dx.doi.org/10.30970/sbi.0802.343
Abstract
Abnormal oligomerisation and aggregation of the protein called alpha-synuclein (α-syn) are the key events in the pathogenesis of Parkinson’s disease (PD). Recent discoveries revealed cellular pathways that potentially relate neurodegenerative disease (ND) to abnormal functioning of mitochondria or anomalous glucose metabolism. In this study we describe for the first time strains of the thermotolerant methylotrophic yeast Hansenula polymorpha that produce human GFP-tagged α-syn as a new model of molecular processes leading to PD. We observed that NCYC495-SNCA wild-type strain did not form visible α-syn amyloid-like aggregates but exhibited plasma membrane perforations and cytoplasm leakage. gcr1-2-SNCA mutant strain deficient in catabolite repression and glucose transport exhibited enhanced aggregation of fluorescently tagged α-syn. However, the observed differences did not result from the impaired glucose metabolism as were observed in both α-syn-producing strains grown on glycerol. Production of α-syn was detrimental for both strains and decreased their growth rate on alternative carbon sources. Our data suggests that H. polymorpha may serve as an informative new yeast model for deciphering molecular mechanisms of PD that regulate amyloid formation and degradation under the influence of various extra- and intracellular factors.
Keywords
Full Text:
PDFReferences
1. Aviles-Olmos I., Limousin P., Lees A., Foltynie T. Parkinson's disease, insulin resistance and novel agents of neuroprotection. Brain, 2012; 136(Pt 2): 374-84. | |
| |
2. Baltic S., Perovic M., Mladenovic A. et al. α-syn Is Expressed in Different Tissues During Human Fetal Development. Journal of Molecular Neuroscience, 2004; 22(3): 199-203. | |
| |
3. Beyer K. Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol, 2006; 112(3): 237-51. | |
| |
4. Bocer T., Zarubica A., Roussel A. The mammalian ABC transporter ABCA1 induces lipid-dependent drug sensitivity in yeast. Biochimica et Biophysica Acta (BBA), 2012; 1821(3): 373-380. | |
| |
5. Bodner R.A., Outeiro T.F., Altmann S. et al. Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington's and Parkinson's diseases. PNAS, 2004; 103(11): 4246-4251. | |
| |
6. Chen L., Periquet M., Wang X. et al. Tyrosine and serine phosphorylation of α-syn have opposing effects on neurotoxicity and soluble oligomer formation. J. Clin. Invest, 2009; 119: 3257-3265. | |
| |
7. Emadi S., Barkhordarian H., Wang M. S. et al. Isolation of a human single chain antibody fragment against oligomeric α-syn that inhibits aggregation and prevents α-syn induced toxicity. J. Mol. Biol, 2007; 368(4): 1132-1144. | |
| |
8. Faber K.N., Haima P., Harder W. et al. Highly-efficient electrotransformation of the yeast Hansenula polymorpha. Curr. Genet,1994; 25: 305-310. | |
| |
9. Franssens V., Bynens T., Van den Brande J. et al. The benefits of humanized yeast models to study Parkinson's disease. Oxidative Medicine and Cellular Longevity (Hindawi Publishing Corporation), 2013; 2013: Article ID 760629, 9 pages. | |
| |
10. Gellissen G. Heterologous protein production in methylotrophic yeasts. Appl. Microbiol, 2000; Biotechnol. 54: 741-750. | |
| |
11. Hashimoto M., Rockenstein E., Crews L., Masliah E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. Neuro Molecular Medicine, 2003; 4: 21-35. | |
| |
12. Kayed R., Sokolov Y., Edmonds B. et al. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases, J. Biol. Chem, 2004; 279: 46363-46366. | |
| |
13. Krasovska O.S., Stasyk O.G., Nahorny V.O. et al. Glucose-induced production of recombinant proteins in Hansenula polymorpha mutants deficient in catabolite repression. Biotechnol. Bioeng, 2007; 97: 858-870. | |
| |
14. Lashuel H.A., Hartley D., Petre B.M. et al. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature, 2002; 418(6895): 291. | |
| |
15. Lücking C.B., Brice A. Alpha-synuclein and Parkinson's disease. Cell. Mol. Life Sci, 2000; 57: 1894-1908. | |
| |
16. Monastryska I., Sjollema K., Van-Der-Klei I. J. et al. Microautophagy and macropexophagy may occur simultaneously in Hansenula polymorpha. FEBS Letters, 2004; 568(1-3): 135-138. | |
| |
17. Norris E.H., Giasson B. I., Lee V.M.-Y. Synuclein: normal function and role in neurodegenerative diseases. Curr Top Dev Biol, 2004; 60: 17-54. | |
| |
18. Ocampo A., Barrientos A. Developing yeast models of human neurodegenerative disorders. Methods Mol Biol, 2011; 793: 113-27. | |
| |
19. Pacheco C., Aguayo L.G., Opazo C. An extracellular mechanism that can explain the neurotoxic effects of α-syn aggregates in the brain. Front. Physiol, 2012; 3: 297. | |
| |
20. Pieri L., Madiona K., Bousset L., Melki, R. Fibrillar alpha-synuclein and huntingtin exon 1 assemblies are toxic to the cells. Biophys. J, 2012; 102: 2894-2905. | |
| |
21. Ross C.A., Poirier M.A. Protein aggregation and neurodegenerative disease. Nat. Med, 2004; 10: S10-S17. | |
| |
22. Sambrook J., Russel D. Molecular cloning: a laboratory manual. 3rd ed. Cold Spring Harbor Laboratory, 2001. 3 vol.: 510 p. | |
| |
23. Sandyk R. The relationship between diabetes mellitus and Parkinson's disease. Intern. J. Neuroscience, 1993; 69: 125-130. | |
| |
24. Santangelo G. Glucose signaling in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev, 2006; 70(1): 253-258. | |
| |
25. Stasyk O.V., Stasyk O.G., Komduur J. et al. A hexose transporter homologue controls glucose repression in the methylotrophic yeast Hansenula polymorpha. J. Biol. Chem, 2004; 279(9): 8116-25. | |
| |
26. Sun Y., Chang Y.-H., Chen H.-F. et al. Risk of Parkinson Disease Onset in Patients With Diabetes. Diabetes Care, 2012; 35(5): 1047-1049. | |
| |
27. Tenreiro S., Outeiro T.F. Simple is good: yeast models of neurodegeneration. FEMS Yeast Res, 2010; 10: 970-979. | |
| |
28. Uéda K., Saitoh T., Mori H. Tissue-dependent alternative splicing of mRNA for NACP, the precursor of non-A beta component of Alzheimer's disease amyloid. Biochem. Biophys. Res. Commun, 1994; 205(2): 1366-72. | |
| |
29. Vekrellis K., Xilouri M., Emmanouilidou E. et al. Pathological roles of α-syn in neurological disorders. Lancet Neurol, 2011; 10(11): 1015-25 | |
| |
30. Volles M.J., Lee S.-J., Rochet J.-C. et al. Vesicle permeabilization by protofibrillar α-syn: implications for the pathogenesis and treatment of Parkinson's disease. Biochemistry, 2001; 40: 7812-7819. | |
| |
31. Waxman E. A., Giasson B. I. Molecular mechanisms of α-syn neurodegeneration. Biochimica et Biophysica Acta (BBA), 2009; 1792: 616-624. | |
| |
32. Xu Q., Park Y., Huang X. et al. Diabetes and risk of Parkinson's disease. Diabetes Care, 2011; 34: 910-815. | |
| |
33. Zakharov S.D., Hulleman J.D., Dutseva E A. et al. Helical alpha-synuclein forms highly conductive ion channels. Biochemistry, 2007; 46: 14369-14379. | |
Refbacks
- There are currently no refbacks.
Copyright (c) 2014 Studia biologica
This work is licensed under a Creative Commons Attribution 4.0 International License.