Baker Lab scientist Vikram Mulligan describes how Foldit can help Alzheimer's disease research
Alzheimer's disease is an invariably fatal neurodegenerative disease that is now the seventh most common cause of death in Canada and the United States. Currently, one death in thirty-six is attributable to this disease. There is no cure for Alzheimer's, and existing treatments only provide temporary symptomatic relief, doing little to affect disease progression or longevity. Like most of the late-onset neurodegenerative dieases, Alzheimer's disease has protein misfolding and aggregation at its root. The Aβ polypeptide, a byproduct of protein cleavage that is produced continuously in the human brain and released into the extracellular space, self-associates to form toxic, soluble complexes (oligomers) and insoluble masses (aggregates). Although this self-assembly and aggregation process is poorly understood, one or more of the oligomeric or aggregated forms of Aβ produced along this pathway is toxic to neurons. Eventually, enough of this material accumulates to trigger massive neuronal loss in the brain, resulting in progressive dementia and, eventually, death.
Although small-molecule drugs are being developed to target downstream events in order to protect neurons, it would be better to target the root cause, if we could. Unfortunately, it is extremely difficult to prevent the self-association of large polypeptide chains into enormous aggregates using small molecules, since small molecules do not present enough surface area to compete with proteins that are prone to self-association. For this reason, we wish to develop protein therapeutics that can compete with self-assembly in order to target the Aβ aggregation cascade at the root of Alzheimer's disease.
Such a project will involve many challenges: getting the protein into the body and across the blood-brain barrier, having it evade the immune system, and ensuring that it persists long enough to have a desired effect will be just a few. A first step in this will involve the creation of a small protein able to bind tightly and specifically to monomeric Aβ, preventing Aβ self-association. Later stages will involve attempts to add functionality to the binder, in order to promote Aβ clearance or degradation.
As a starting point, we will be using an affibody molecule created in 2007 by a group at the Swedish Royal Institute of Technology (KTH) [1,2]. This molecule was created in a structure-agnostic manner, by screening a combinatorial library for Aβ binders, and was subsequently found to bind as a homodimer (i.e. two identical protein molecules bind a single Aβ molecule). Unfortunately, this means that a symmetric interface binds an asymmetric Aβ molecule, limiting the affinity and specificity of the binder for Aβ. We would like FoldIt players to redesign this two-chain molecule as one long polypeptide chain, breaking the symmetry of the interface and improving its affinity by separately optimizing both sides of the interface for the part of the Aβ molecule that each touches. The initial puzzle involves redesigning interface and core residues for optimal binding. Subsequent steps will involve designing new loops to connect the two subunits.
1. Grönwall C, Jonsson A, Lindström S, Gunneriusson E, Ståhl S, Herne N. (2007) Selection and characterization of Affibody ligands binding to Alzheimer amyloid beta peptides. J Biotechnol. 128(1):162-83.
2. Hoyer W, Grönwall C, Jonsson A, Ståhl S, Härd T. (2008) Stabilization of a beta-hairpin in monomeric Alzheimer's amyloid-beta peptide inhibits amyloid formation. Proc Natl Acad Sci U S A. 105(13):5099-104.