Research

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Basic Mechanism:

Protein misfolding diseases are characterized by the deposition of endogenous proteins in the affected tissue. While the proteins that are involved in protein misfolding diseases, such as Alzheimerís disease, Parkinsonís disease or Cretzfeldt-Jakob disease are characteristic for each disease, the mechanism by which they form deposits is strikingly similar.

 

Proteins, such as a-synuclein and the amyloid-b (Ab) peptides self-assemble in a stepwise process that can be described as Ďnucleated polymerizationí. During a nucleation phase, the equilibrium of nascent assemblies with monomeric protein lies mostly on the side of the monomer. In constrast, fibrillar structures of a certain size have sufficient stability, so that monomer addition is strongly favored over dissociation, which leads to rapid growth of fibrillar assemblies.

 

Our lab is trying to quantify the kinetic and thermodynamic parameters of self-assembly in biological systems, and to characterize how these affect internalization, growth, and degradation of amyloid structures in the cell. Mechanistic understanding is also the prerequisite for developing new therapeutic strategies  against protein misfolding diseases.

 

 

 

 

 

 

 

 

 

Therapeutic intervention:

We are interested in developing new therapeutic strategies against protein misfolding disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), have in common that a protein accumulates in an insoluble form in the affected tissue. Although the toxic species is still ill defined, the process rather than the end product of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on removing the amyloidogenic protein (1) or depleting aggregation intermediates rather than inhibiting or reversing the formation of large fibrillar aggregates (2).

 

Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG) binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead it promotes the formation of stable, spherical aggregates (3). These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, EGCG remodels amyloid fibrils into aggregates with the same properties.

 

Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Rocella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the AD-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide (4). These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

 

 

 

 

 

 

 

 

 

 

 

 

 

Ehrnhoefer, D. E., J. Bieschke, et al. (2008). "EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers." Nat Struct Mol Biol 15(6): 558-66.

Bieschke, J., J. Russ, et al. (2010). "EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity." Proc Natl Acad Sci U S A 107(17): 7710-5.

Bieschke, J., M. Herbst, et al. (2011). "Small molecule mediated conversion of toxic oligomers to non-toxic amyloid fibrils." Nature Chemical Biology:

 

 

 

 

Lichen Roccella tinctoria found on the Canary islands (photo courtesy of Prof. Anders Tehler, Naturhistoriska riksmuseet, Stockholm)

Age-Related Protein Misfolding

Laboratory of Jan Bieschke, Ph.D.

Center for Biological and Systems Engineering

Our lab studies the mechanisms of protein misfolding and aggregation in aging-related diseases such as Alzheimerís and Parkinsonís disease using a three part approach:

 

1. Basic Mechanism

 

2. Proteomic Modulation

 

3. Therapeutic Intervention