Professor

Education

Graduate in Biological Sciences. University of Chile, School of Sciences. 1986.

PhD in Biological Sciences with mention in Biochemistry. University of Chile, School of Sciences. 1992.

Post-doctoral research in Neurobiology, working in cellular processing of the amyloid precursor protein in Alzheimer's disease. Molecular Neurobiology Unit, Catholical University of Chile 1992-1994. Sponsor: Dr. Nibaldo C. Inestrosa.

Post-doctoral research in Neuroscience, working in the biochemistry of amyloid formation in Alzheimer's disease. Dept. of Pathology, New York University Medical Center 1994-1995. Sponsor: Dr. Blas Frangione.

Special Interests

For the last 10 years, Dr. Soto’s group has been studying the molecular basis of neurodegenerative disorders, mainly focusing in Alzheimer’s disease (AD) and in Transmissible Spongiform Encephalopathies (TSE). A hallmark event in both AD and TSE is the misfolding of a natural protein, which acquires a toxic activity and the ability to aggregate and deposit in the brain. We have been studying the mechanisms of protein misfolding and aggregation and their implication in neurodegeneration as well as developing novel therapeutic and diagnostic strategies for these diseases.
Dr. Soto’s group developed a new model to explain amyloidogenesis in AD brains, which proposes that amyloid formation is triggered by conformational changes in the normal amyloid-ß protein. We also identified some of the factors that may induce in vivo the misfolding of the amyloid-ß protein and provided strong evidences that at least some of them (for example apolipoprotein E, RAGE receptor, ERAB protein) might play a critical role in vivo. Based on the data generated by us and other groups, AD is now included in the group of disorders involving protein conformational changes as a key event in the pathogenesis.

Based on the knowledge of the structural determinants for protein misfolding, we have developed a novel strategy to correct protein misfolding and aggregation for both AD and TSE. The strategy consists in designing compounds with the capability to interact specifically with the misfolded protein and destabilize its pathological ß-sheet rich conformation. These compounds, called ß-sheet breakers, have been demonstrated to be active in vitro and in transgenic animal models for AD and in scrapie models of TSE. We have characterized and improved their pharmacological properties to make them suitable for in vivo use in CNS diseases. Indeed, the first ß-sheet breaker compound is currently under clinical evaluation in humans affected by AD.

We have also recently developed the concept of cyclic amplification of protein misfolding (PMCA) to replicate in vitro the pathological process associated to these diseases in a rapid and efficient way. The PMCA technology has been applied to convert large amounts of the normal prion protein into the abnormal form by incubating it with minute amounts of abnormal prion protein. These findings mark the first time in which the folding and biochemical properties of a protein have been cyclically amplified in a manner conceptually analogous to the amplification of DNA by PCR. PMCA might be helpful to understand the underlying biology of prions, to identify other factors that may be responsible for prion protein conversion, and to discover novel drug targets for TSEs. In addition, PMCA has enormous potential in allowing current diagnostic tools to detect BSE and vCJD during the pre-symptomatic period and perhaps in living individuals. Using this technology, we have recently provided the most compelling evidence for the prion hypothesis, consisting on the generation of infectious prions in vitro after amplification.

The principles to design ß-sheet breaker peptides and PMCA could constitute platform technologies to produce therapies and diagnosis procedures for many other diseases involving protein conformational changes.

Finally, we are also studying the cellular factors involved in protein misfolding and aggregation, the mechanism of neuronal apoptosis and the role of brain inflammation in neurodegenerative diseases. Our recent accomplishments in this area include the identification of a potential pathway by which misfolded proteins can induce neuronal apoptosis. This pathway involves endoplasmic reticulum stress, release of intracellular calcium, upregulation of ER stress chaperones, activation of caspase-12 and finally induction of caspase-3 activity.

Selected Publications

(Selected from more than 70)
1.  Castilla, J., Saa, P., Hetz, C. and Soto, C. (2005) In vitro generation of infectious scrapie prions. Cell (in press)

2.  Hetz, C., Russelakis-Carneiro, M., Walchli, S., Carboni, S., Vial- Knecht, E., Maundrell, K. and Soto, C. (2005) The disulfide isomerase Grp58 is a neuroprotective factor against prion replication. J. Neurosci. (in press)

3.  Soto, C. (2004) Diagnosing prion diseases: needs, challenges and hopes. Nature Rev. Microbiol. 2: 809-819. Selected article of the month by the editors.

4.  Soto, C. and Castilla, J. (2004) The controversial protein-only hypothesis of prion propagation. Nature medicine 10: S63-S67.

5.  Soto, C. (2003) Unfolding the role of Protein Misfolding in Neurodegenerative Diseases. Nature Rev. Neurosci. 4: 49-60.

6.  Hetz, C., Russelakis, M., Maundrell, K., Castilla, J. and Soto, C.(2003) Neuronal apoptosis induced by pathological prion protein is mediated by caspase-12 and endoplasmic reticulum stress. EMBO J. 22: 5436-5445. (Highlighted in Science)

7.  Permanne, B., Adessi, C., Saborio, G.P., Fraga, S., Frossard, M.J., Van Dorpe, J., Dewachter, I., Banks, W.A., Van Leuven, F. and Soto, C. (2002) Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer’s disease by treatment with a ß-sheet breaker peptide. FASEB J. 16: 860-862.

8.  Soto, C. (2001) Protein misfolding and disease; Protein refolding and therapy. FEBS Lett 498: 204-207.

9.  Saborio, G.P., Permanne, B. and Soto, C. (2001) Cyclic amplification of protein misfolding: A novel approach for sensitive detection of pathological prion protein. Nature 411: 810-813. (Selected article of the week by Nature editors).

10.  Soto, C., Kascsak, R.J., Saborio, G., Aucouturier, P., Wisniewski, T., Prelli, F., R. Kascsak, Mendez, E., Harris, D.A., Ironside, J., Tagliavini, F., Carp, R.I. and Frangione, B. (2000) Reversion of prion protein conformational changes by synthetic ß-sheet breaker peptides. The Lancet 355: 192-197.

11.  Soto, C., Sigursson, E., Morelli, L., Kumar, R.A., Castaño, E.M. and Frangione, B. (1998) ß-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer’s therapy. Nature med. 4: 822-826.

12. Yan, S.D., Fu, J., Soto, C., Chen, X., Zhu, H., Al-Mohanna, F., Collison, K., Zhu, A., Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A. and Stern, D. (1997) A novel intracellular amyloid-beta peptide binding protein which mediates neurotoxicity in Alzheimer’s disease. Nature 389: 689-698.

13. Inestrosa, N.C., Alvarez, A., Perez, C.A., Moreno, R.D., Vicente, M., Linker, C., Soto, C., and Garrido, J. (1996) Acetylcholinesterase accelerates assembly of amyloid- ß peptides into Alzheimer's amyloid fibrils: Possible role of the peripheral binding site of the enzyme. Neuron 16: 881-891.

14. Soto, C., Castaño, E.M., Frangione, B. & Inestrosa, N.C. (1995) The ?-helical to ß-stand transition in the N-terminal fragment of the amyloid? ß-peptide modulates amyloid formation. J. Biol. Chem. 270: 3063-3067.

15. Soto, C.(2003) Unfolding the role of Protein Misfolding in Neurodegenerative Diseases. Nature Rev. Neurosci. 4: 49-60.

16. Hetz, C., Russelakis, M., Maundrell, K., Castilla, J. and Soto, C. (2003) Neuronal apoptosis induced by pathological prion protein is mediated by caspase-12 and endoplasmic reticulum stress. EMBO J. 22: 5436-5445.

17. Permanne, B., Adessi, C., Saborio, G.P., Fraga, S., Frossard, M.J., Van Dorpe, J., Dewachter, I., Banks, W.A., Van Leuven, F. and Soto, C. (2002) Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer’s disease by treatment with a ß-sheet breaker peptide. FASEB J. 16: 860-862 (full-version published online on April 10, 2002 as 10.1096/fj.01-0841fje).

18. Soto, C. (2001) Protein misfolding and disease; Protein refolding and therapy. FEBS Lett 498: 204-207.

19. Saborio, G.P., Permanne, B. and Soto, C. (2001) Cyclic amplification of protein misfolding: A novel approach for sensitive detection of pathological prion protein. Nature 411: 810-813. (Selected article of the week by Nature editors).

20. Soto, C., Kascsak, R.J., Saborio, G., Aucouturier, P., Wisniewski, T., Prelli, F., R. Kascsak, Mendez, E., Harris, D.A., Ironside, J., Tagliavini, F., Carp, R.I. & Frangione, B. (2000) Reversion of prion protein conformational changes by synthetic ß-sheet breaker peptides. The Lancet 355: 192-197.

21. Soto, C., Sigursson, E., Morelli, L., Kumar, R.A., Castaño, E.M. and Frangione, B. (1998) ß-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer’s therapy. Nature med. 4: 822-826.

22. Soto, C., Golabek, A., Wisniewski, T. & Castaño, E.M. (1996) Alzheimer's ß-amyloid peptide is conformationally modulated by apolipoprotein E in vitro. NeuroReport 7: 721-725.

23. Soto, C., Castaño, E.M., Frangione, B. & Inestrosa, N.C. (1995) The a-helical to ß-stand transition in the N-terminal fragment of the amyloidß-peptide modulates amyloid formation. J. Biol. Chem. 270: 3063-3067.

E-Mail: clsoto@utmb.edu