Molecular Biophysics I
2005
Session #13

Protein Misfolding I
 Prions and 'Mad-Cow' Disease

Instructor: T. P. Monson, M.D.

April 27, 2005
BioMed 205/207
1:00 p.m. - 3:50 p.m.

Tom Monson, an infectious disease expert at UAMS & the Little Rock VA Hospital, will summarize recent results concerning the prion diseases in humans, and attempt to relate the the basic science data to the clinical situation.

As background for Dr. Monson's presentation, I have listed three review papers on the mammalian prion story, two by Stanley Prusiner (who received the 1997 Nobel prize in Physiology & Medicine for work associated with his 'prion hypothesis') and a more recent  update by Aguzzi & Polymenidou.

References

1.    Prusiner, SB, Scott, M. R., DeArmond, S. J., and Cohen, F. E., Prion protein biology. Cell 93: 337-488, 1998.

2.    Prusiner, SB, Prions. Proceedings.of the National.Academy.of Sciences 95: 13363-13383, 1998.

3.    Aguzzi, A and Polymenidou, M., Mammalian prion biology: One century of evolving concepts. Cell 116:
       313-327,  2004.

Molecular Biophysics I
2005
Session #14

Protein Misfolding II
 Recent Results with Yeast Prions

May 04, 2005
BioMed 205/207
1:00 p.m. - 3:50 p.m.

In this session, we first take time to address several questions that arose last time, concerning mammalian prions, specifically:

1. Detection of PrPSc using immunologic means (e.g., diagnosis of CJD):

See: Safar,J.G. et al. [Prusiner group, UCSF] (2005). Diagnosis of human prion disease.
Proc. Natl. Acad. Sci. U. S. A 102, 3501-3506;

2. Prevention of iatrogenic transmission of prions & the decontamination of surgical instruments

Jackson,G.S., McKintosh,E., Flechsig,E., Prodromidou,K., Hirsch,P., Linehan,J., Brandner,S., Clarke,A.R., Weissmann,C., and Collinge,J. (2005). An enzyme-detergent method for effective prion decontamination of surgical steel. J. Gen.Virol.   86, 869-878.

3. Structurally-unstable polypeptides may be stabilized… transiently…only to cause problems later:
       (Example: Figure 8, based on data obtained with mutants of TTR)

Sekijima,Y., Wiseman,R.L., Matteson,J., Hammarstrom,P., Miller,S.R., Sawkar,A.R., Balch,W.E., and Kelly,J.W. (2005). The biological and chemical basis for tissue-selective amyloid disease. Cell 121, 73-85;

Prions also are found in yeast, where they are transmissible (mother to daughter cells) but do not seem to be pathogenic. Structurally, the yeast & mammalian prion proteins share a common feature: the presence of amino acid sequences capable of  forming amyloid fibrils. Thus, study of the biophysics of amyloid formation using the yeast prions may shed light on amyloid formation in humans, and provide a mechanistic basis for developing more effective therapeutic strategies for mammalian prion-associated diseases.

References

        1.   Osherovich, L.Z., Cox, B.S., Tuite, M. F., and Weissman, J. S., Dissection and design of yeast prions. PLoS Biology 2: 0442-0451, 2004.

        2.   Collins, SR, Douglass, A., Vale, R. D., and Weissman, J. S., Mechanism of Prion Propagation: Amyloid Growth             Occurs by Monomer Addition. PLoS Biology 2: E321-(9 pages), 2004.

        3.   Shorter, J and Lindquist, S., Hsp104 Catalyzes Formation and Elimination of Self-Replicating Sup35 Prion Conformers. Science 304: 1793-1797, 2004.