Alfred Goldberg

This talk will focus on the diversity of human diseases that are associated with problems with protein folding. The main focus of this talk will be on the various cellular mechanisms that help prevent the continued accumulation of abnormal (denatured) proteins in the cytosol, nucleus, mitochondria and secretory pathway. The intracellular milieu is not conducive to protein stability, and mutations, biosynthetic errors, intracellular damage and denaturation, failure of normal polypeptides to fold properly or a failure of the proteolytic machinery of a cell can all lead to a build-up of potentially damaging polypeptides.

Of particular importance in protecting against misfolded proteins is protein degradation by the ubiquitin–proteasome pathway and by ATP-dependent proteases. This proteolytic machinery functions together with molecular chaperones to selectively eliminate abnormal proteins, the continued build-up of which in the cytosol or ER can cause cellular misfunction or trigger apoptosis. Although many diseases (for example, several major neurodegenerative diseases and many haemoglobinopathies) seem to result from proteins escaping this quality-control system, the very efficient degradation of partially folded protein (for example, mutant cystic fibrosis transmembrane conductance regulator (CFTR)) can also cause diseases (for example, cystic fibrosis).

Moderator: Chris Dobson, University of Cambridge

The session will consider approaches to monitoring dynamic protein structures both in vitro and in vivo. What can we learn from studying model systems? How does mutational analysis help us to understand folding and disease? What methods are available to study structural details of proteins in vivo? And lastly, as a prelude to the discussion topic that follows, what is the link between protein folding and protein engineering and design?

Key questions

Moderator: Ari Helenius, ETH-Hoenggerberg

How does the cellular milieu influence protein folding, and how, indeed, do misfolded proteins influence the cell? Key questions to be addressed will include the role of chaperones in controlling the formation and fate of folded proteins, and how covalent modifications, both co-translational and post-translational, affect the process. Time will be given to consideration of the special role of the endoplasmic reticulum as a site of protein folding, and to close the session, discussion will focus on cellular responses to protein misfolding.

Key questions

Moderator: Denis Selkoe, Brigham and Women's Hospital

This session will concentrate on the process of protein aggregation and the toxicity of polymeric assemblies of misfolded proteins. In the pathogenesis of the amyloidoses, do monomers misfold and then polymerize into fibrils, or do monomers begin to oligomerize first and then assume the b-pleated sheet structure? Would misfolded proteins that accumulate in the cytoplasm be expected to undergo a distinct kind of aggregation process to those in the extracellular space, and, if so, how might they differ? Is progressive neuronal degeneration in the protein misfolding diseases attributable to the effects of misfolded monomers, oligomers or (microscopically visible) polymers of the respective proteins?

Key questions

Moderator: Fred Cohen, University of California, San Francisco

What are the challenges for drug discovery in aggregation diseases? What are the roles for antibodies versus small molecules? If, as some recent work indicates, the tendency to form b-sheet-rich aggregates is a generic property of polypeptides, will there be generic inhibitors of this process that could have pharmaceutical implications? What are the best systems for screening for inhibitors of aggregation and will such inhibitors have the desired therapeutic effect if, indeed, oligomeric aggregates are the toxic isoforms. Finally, the discussion will open out to consider how we generalize from therapeutics for diseases such as familial amyloidotic polyneuropathy to some of the more common diseases of protein aggregation.

Key questions