An ankyrin repeat chaperone targets toxic oligomers during amyloidogenesis

Numerous age-linked diseases are rooted in protein misfolding; this has motivated the development of small molecules and therapeutic antibodies that target the aggregation of disease-linked proteins. Here we explore another approach: molecular chaperones with engineerable protein scaffolds such as the ankyrin repeat domain (ARD). We tested the ability of cpSRP43, a small, robust, ATP- and cofactor-independent plant chaperone built from an ARD, to antagonize disease-linked protein aggregation. cpSRP43 delays the aggregation of multiple proteins including the amyloid beta peptide (A beta) associated with Alzheimer's disease and alpha-synuclein associated with Parkinson's disease. Kinetic modeling and biochemical analyses show that cpSRP43 targets early oligomers during A beta aggregation, preventing their transition to a selfpropagating nucleus on the fibril surface. Accordingly, cpSRP43 rescued neuronal cells from the toxicity of extracellular A beta 42 aggregates. The substratebinding domain of cpSRP43, composed primarily of the ARD, is necessary and sufficient to prevent A beta 42 aggregation and protect cells against A beta 42 toxicity. This work provides an example in which an ARD chaperone non-native to mammalian cells harbors anti-amyloidal activity, which may be exploited for bioengineering.