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Mednarodna
podiplomska šola
Jožefa Stefana

Jamova 39
SI-1000 Ljubljana
Slovenija

Tel: (01) 477 31 00
Faks: (01) 477 31 10
E-pošta: info@mps.si

Išči

Opis predmeta

Mehanizem in biološke implikacije agregacije proteinov

Programi:

Nanoznanosti in nanotehnologije, 3. stopnja

Sodelavci:

prof. dr. Eva Žerovnik

Cilji:

Razumeti proces agregacije proteinov do amiloidnih fibril. Ti procesi se pojavljajo v nevrodegenerativnih boleznih kot so Alzheimerjeva, Parkinsonova, razne demence in prionske bolezni. Z boljšim razumevanjem molekularnih in celičnih osnov proteinske agregacije bo možno priti do novih terapij za nevrodegenerativne bolezni. Predmet bo vključeval molekularne, celične in izbrane klinične vidike.

Vsebina:

Poglavja:

1. Biofizikalne osnove agregacije proteinov
(Modeli za amiloidno fibrilacijo proteinov)
2. Struktura amiloidnih fibril
3. Eksperimentalne tehnike za študij termodinamike in kinetike procesa fibrilacije
(Študij primerov iz literature: A-beta, beta-microglobulin, alfa-sinuklein, stefin B.)
4. Korelacija med zvijanjem proteinov in tvorjenjem amiloidnih fibril (Vloga vmesnih stanj zvitja pri tvorbi amiloidov; Vloga šaperonov pri obrambi pred agregati)
5. Citotoksičnost amiloidnih fibril (Interakcija z lipidi in tvorjenje por)
6. Proteinska agregacija v celici (Akumulacija in transport agregatov; Čiščenje celice – razgradnja agregatov preko ubikvitin proteasomalnega sistema in autofagije)
7. Amiloidoze in nevrodegenerativne bolezni (Seminar)

Temeljna literatura in viri:

Basics

Textbook: Methods Enzymol. 309, Amyloids, Prions and other protein aggregates, ed. Wetzel R.,(1999) Academic Press.

Textbook: Amyloid Proteins; Methods and Protocols Ed. Sigurdsson EM, Series: Methods in Molecular Biology Vol 299, Humana Press 2005.

Texbook: Molecular Chaperones in the Cell, Frontiers in Mol.Biology series, ed. P. Lund, Oxford Univ.Press, 2001

Textbook: R.H. Pain: Mechanisms of Protein Folding, 2nd edn., (2000) R. H. Pain (ed.), Oxford University Press, ISBN 0 19 963788, selected chapters.

Additional Textbook: Protein Folding-Misfolding: some current concepts of protein chemistry. (2007) Zbilut JP and Scheibel T (eds.), Nova Sci Publi., New York.

Additional Textbook: Protein misfolding diseases; current and emerging therapies. eds Raminez-Alvarado, J.W. Kelly, C.M. Dobson, Wiley Series in Protein and Peptide Science, Series Ed. V.N. Uversky. John Wiley & Sons, New Jersey 2010.

Review papers :

Rochet JC and Lansbury PT (2000) Amyloid fibrillogenesis: themes and variations. Curr.Opin.Struct.Biol. 10, 60 – 68.

Sherman MY and Goldberg AL (2001) Cellular defences against unfolded proteins : a cell biologist thinks about neurodegenerative diseases. Neuron 29, 15-32.

Žerovnik E (2002) Amyloid-fibril formation; Proposed mechanisms and relevance to conformational disease. Eur.J.Biochem. 269, 3362- 3371.

Lansbury PT, Lashuel HA. (2006) A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 443: 774-779. Review.

Lashuel HA, Lansbury PT Jr. (2006) Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins? Q Rev Biophys. 39, 167-201.

David C. Rubinsztein (2006) The roles of intracellular protein-degradation pathways in neurodegeneration NATURE 443, 780-786.

Haass C, Selkoe DJ. 2007. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12. Review.

M, Ueno T, Waguri S et al. 2007. Constitutive autophagy:vital role in clearance of unfavorable proteins in neurons. Cell Death Differ. 1-8.

Irvine CB, El-Agnaf OM, Shankar GM and Walsh DM (2008). Protein aggregation in the brain. The molecular basis for Alzheimer’s and Parkinson’s diseases. Mol.Med. 14, 451 – 464.

Additional references available for students.

Izbrane reference nosilca:

1. Book chapter: Žerovnik, E, Giannini, S, Stoka, V, Tušek-Žnidarič, M, Pompe-Novak, M, Staniforth, RA. (2006) On the mechanism of amyloid-fibrillation: stefin B as a good model protein. In: Žerovnik, E, Kopitar-Jerala, N (eds.). Human stefins and cystatins. New York: Nova Sci.Publ., Inc., 2006, pp. 97-114.

2. Rabzelj, S., Viero, G., Gutiérrez-Aguirre, I., Turk, V., Dalla Serra, M., Anderluh, G., Žerovnik, E. (2008) Interaction with model membranes and pore formation by human stefin B - Studying the native and prefibrillar states. FEBS Journal, 275, 2455-2466.

3. Čeru S et al., Žerovnik E. (2008) Size and morphology of toxic oligomers of amyloidogenic proteins: a case study of human stefin B. Amyloid, 15, 147–159.

4. Žerovnik, E., Škarabot, M., Škerget, K., Giannini, S., Stoka, V., Jenko-Kokalj, S., Staniforth, R.A. (2007) Amyloid fibril formation by human stefin B: Influence of pH and TFE on fibril growth and morphology Amyloid, 14, 237-247.

5. Rabzelj, S., Turk, V., Žerovnik, E. (2005) In vitro study of stability and amyloid-fibril formation of two mutants of human stefin B (cystatin B) occurring in patients with EPM1. Protein Science, 14 (10), pp. 2713-2722.

6. Jenko, S., Škarabot, M., Kenig, M., Gunčar, G., Muševič, I., Turk, D., Žerovnik, E. (2004) Different Propensity to Form Amyloid Fibrils by Two Homologous Proteins - Human Stefins A and B: Searching for an Explanation (2004) Proteins: Structure, Function and Genetics, 55, 417-425.

7. Žerovnik, E., Pompe-Novak, M., Škarabot, M., Ravnikar, M., Muševič, I., Turk, V. (2002a) Human stefin B readily forms amyloid fibrils in vitro (2002) Biochimica et Biophysica Acta - Protein Structure and Molecular Enzymology, 1594, 1-5.

Additional, new References:

8. Jelinska C, Davis PJ, Kenig M, et al. (2011) Modulation of Contact Order Effects in the Two-State Folding of Stefins A and B. Biophys.J. 100: 2268-2274.

9. Taler-Verčič A, Žerovnik E (2010) Binding of amyloid peptides to domain-swapped dimers of other amyloid-forming proteins may prevent their neurotoxicity. BIOESSAYS 32: 1020-1024.

10. Škerget K, Taler-Verčič A, Bavdek A, et al. Žerovnik E (2010) Interaction between Oligomers of Stefin B and Amyloid-beta in Vitro and in Cells. J.Biol.Chem. 285: 3201-3210.

11. Čeru S, Layfield R, Zavasnik-Bergant T, et al. Žerovnik E (2010). Intracellular aggregation of human stefin B: confocal and electron microscopy study. Biol.Cell 102: 319-334.

12. Žerovnik E, Staniforth RA, Turk D. (2010). Amyloid fibril formation by human stefins: Structure, mechanism & putative functions. BIOCHIMIE 92: 1597-1607.

13. Žerovnik E (2010) Protein Conformational Pathology in Alzheimer's and Other Neurodegenerative Diseases; New Targets for Therapy. Curr. Alz. Res. 7: 74-83.

14. Žerovnik E (2009) The emerging role of cystatins in Alzheimer's disease. BIOESSAYS 31: 597-599.

15. Škerget K, Vilfan A, Pompe-Novak M, et al. Žerovnik E (2009). The mechanism of amyloid-fibril formation by stefin B: Temperature and protein concentration dependence of the rates. PROTEINS: Structure Function and Bioinformatics 74: 425-436.

16. Morgan GJ, Giannini S, Hounslow AM, et al. (2008) Exclusion of the native alpha-helix from the amyloid fibrils of a mixed alpha/beta protein. J. Mol. Biol. 375: 487-498

17. Jenko Kokalj S, Guncar G, Stern I, et al. (2007) Essential role of proline isomerization in stefin B tetramer formation. J.Mol.Biol. 366: 1569-1579.

18. Žerovnik E, Skarabot M, Skerget K, et al. (2007). Amyloid fibril formation by human stefin B: influence of pH and TFE on fibril growth and morphology. AMYLOID 14: 237-247.

Načini preverjanja znanja:

• ustno preverjanje
• pismeni e-seminar

Obveznosti študentov:

• sprotne naloge, ustni izpit, e-seminar

Zunanje povezave: