INHIBITION OF AMYLOID FORMATION: STABILIZATION OF THE FOLDED STATE OF AL PROTEINS

Congo red is a common histological dye well known for its high affinity binding to the cross ß-sheet structure of amyloid fibrils and for giving a characteristic green birefringence under polarized light. Congo red has been used for identifying, as well as quantifying many different amyloid proteins. Several in vitro studies using Congo Red have shown that it can prevent aggregation of monomeric peptides, such as Aß40/42, amylin, and polyglutamine aggregates in Huntington’s disease (Lorenzo 1994, Aitken 2003, and Sanchez 2003).

Our lab is interested in studying light chain amyloidosis (AL), which is characterized by the deposition of monoclonal immunoglobulin light chains in vital organs causing organ failure and death. The deposited proteins are typically variable domain light chain fragments that have not folded properly and as a consequence aggregate into amyloid fibrils. Here we study AL-09, an amyloidogenic monoclonal Ig light chain from a patient with cardiac AL.

Currently, there is no cure for AL; the primary treatment for patients is an autologous bone marrow transplant, however even good candidates for this treatment can have serious side effects. We are interested in looking at small molecules that could either stabilize the native protein or prevent aggregation of the misfolded light chains. Our hypothesis is that Congo red will inhibit aggregation of AL proteins in a similar manner as it inhibits aggregation of other amyloidogenic proteins.