NCB - The Department of Neuroscience and Biology

Claudio Soto, Ph.D.
Professor and Center Director

Cecil H. and Ida M. Green Distinguished University Chair in Neuroscience

• Affiliations:

  Neuroscience and Cell Biology, Neurology, Biochemistry and Molecular Biology

  George P. and Cynthia Woods Mitchell Center for Neurodegenerative Diseases

• Route: 1045,  Medical Research Building Room 10.138
• Tel: (409) 747-0017
• Fax: (409) 747-0020
• clsoto@utmb.edu
• Soto Lab Webpage
• Dr. Soto's Publications
• Dr. Soto's CV

Claudio Soto , Ph.D.

Education

• -Bachelor of Science, University of Chile, 1986
  -Doctor of Philosophy, University of Chile, 1993
  -Post-Doctoral Training, Catholic University of Chile, 1993-1994
• -Post-Doctoral Training, New York University School of Medicine, 1994-1995

About the Lab

Our lab investigates the molecular basis of Protein Misfolding Disorders, mainly focusing in Alzheimer’s disease (AD) and in prion-related disorders. Protein Misfolding Disorders are a recently recognized new group of diseases in which the hallmark event is the misfolding, aggregation and tissue accumulation of a normal protein. This group includes Alzheimer’s disease, transmissible spongiform encephalopathies (TSE) (also known as prion disorders), Huntington disease, serpin-deficiency disorders, haemolytic anaemia, cystic fibrosis, diabetes type II, Amyotrophic Lateral Sclerosis, Parkinson disease, dialysis-related amyloidosis and more than 15 other less well-known diseases.

We 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 the misfolding of the amyloid-ß protein and provided strong evidences that at least some of them (for example apolipoprotein E, RAGE receptor) might play a critical role in vivo. In the last eight years, the lab has been working on strategies for alterating protein misfolding and aggregation in order to learn more about the molecular mechanism of this process and to generate novel approaches for therapy and diagnosis. The work has been built around two important discoveries that represents novel platform technologies: beta-sheet breakers peptides for preventing and correcting protein conformational changes and aggregation (therapeutic use) and the concept of cyclic amplification of protein misfolding for detecting the early pathogenic event in these diseases (diagnosis use).

Based on the knowledge of the structural determinants for protein misfolding, we have developed the concept of ß-sheet breaker peptides for the treatment of protein misfolding diseases. ß-sheet breaker peptides are short synthetic peptides homologous to the fragment of the protein undergoing misfolding, and engineered to contain residues that specifically block and reverse the conformational changes. ß-sheet breakers have been created to correct the misfolding of the amyloid-ß protein and the prion protein. The compounds have been demonstrated to be active in several in vitro and cellular models as well as in transgenic animal models for AD and in scrapie models of prion diseases. We have also characterized and improved the pharmacological properties of these compounds to make them suitable for in vivo use in CNS diseases. The first ß-sheet breaker peptide is currently under clinical evaluation in humans affected by AD.

Cyclic amplification of protein misfolding (PMCA) is considered a major breakthrough in science and technology, because allows to mimic 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. The system consists on cycles of accelerated prion replication to reach an exponential increase in the conversion. 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 prion diseases. 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, because it can multiply the number of prions facilitating their detection. Indeed, recent improvements of the technology has led to a more than 3 billion fold increase on sensitivity and the possibility to detect as few as one single particle of infectious protein. This level of sensitivity has recently enabled us to detect for the first time prions in the blood of sick as well as pre-symptomatic animals. These findings have had a major impact in various fields including the diagnosis of prion disease, blood banks safety, beef industry, etc. In addition, using the PMCA technology we have been recently able to generate infectious prion protein in vitro by propagating the protein misfolding process. Inoculation of wild-type animals with in vitro generated misfolded protein led to a disease with identical biochemical, histological and clinical features as transmissible spongiform encephalopathies. This experiment is widely considered by most scientists in the field as the final and definitive proof for the controversial prion hypothesis and as such is a major breakthrough in science.

Our research has also focused on understanding the mechanism by which misfolded proteins induce cell death and tissue damage. Our recent work has demonstrated that misfolded prion protein induces neuronal apoptosis through endoplasmic reticulum (ER) stress pathway. Interestingly, the initial response to ER-stress is a defense mechanism characterized by the up-regulation of ER chaperones. We have identified one of these chaperones as a key element on this pathway, which is specifically overexpressed in individuals affected by TSE and may lead to a novel strategy for early diagnosis.

Recently, we have become interested in the identification of non-disease-associated proteins undergoing misfolding and aggregation as part of the normal biological function of the protein. Our recent studies show that a bacterial protein normally polymerizes as amyloid-like aggregates which participate in modulating the biological activity of the protein. The expansion of the amyloid and prion concepts towards many other proteins might revolutionize our understanding of biology.

Select Publications

Select Publications (selected from over 100):

Castilla, J., Gonzalez, D., Saa, P., Morales, R., De Castro, J. and Soto, C. (2008) Crossing the species barrier by PrPSc replication in vitro generates new infectious prions. Cell (In press).

Hetz, C., Castilla, J. and Soto, C. (2007) Perturbation of endoplasmic reticulum homeostasis facilitates prion replication. J. Biol. Chem. 282: 12725-12723.

Saa, P., Castilla, J. and Soto, C.. (2006) Ultra-efficient replication of infectious prions by automated protein misfolding cyclic amplification. J. Biol. Chem. 281: 35245-35252.

Saa, P., Castilla, J. and Soto, C. (2006) Pre-symptomatic detection of prions in blood. Science 313: 92-94.

Soto, C., Estrada, L.D. and Castilla, J. (2006) Amyloid, Prions and the inherent infectious nature of misfolded protein aggregates. Trends Biochem. Sci. 31: 150-155.

Castilla, J., Saa, P., Hetz, C. and Soto, C. (2005) In vitro generation of infectious scrapie prions. Cell 121: 195-206.

Bieler, S., Estrada, L., Lagos, R., Castilla, J. and Soto, C. (2005) Amyloid formation modulates the biological activity of a bacterial protein. J. Biol. Chem. 280: 26880-26885.

Castilla, J., Saa, P. and Soto, C. (2005) Biochemical detection of prions in blood. Nature medicine 11: 982-985.

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

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.

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

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.

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.

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.

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 medicine 4: 822-826.

Inestrosa, N.C., Alvarez, A., Perez, C.A., Moreno, R.D., Vicente, M., Linker, C., Soto, C. (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.

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.