(76d) The Amyloid Regulatory Network Hypothesis

“Amyloid” is a general term describing protein aggregates with several physicochemical features in common: fibrillar morphology, predominantly cross b-sheet secondary structure, and protease resistance. Deposits of aggregated protein are linked to several degenerative disorders including Huntington’s, Alzheimer’s, Parkinson’s, and prion diseases. These deposits may be extracellular (e.g., in Alzheimer’s) or intraneuronal (e.g., in Huntington’s). Despite the shared fibrillar morphology, the proteins involved have no sequence homology or common native fold, and the specific cellular sub-types affected in each disorder are unique. Numerous in vitro and animal studies provide support for the ‘amyloid cascade hypothesis’ – that aggregation is causally linked to cellular toxicity. At one time it was believed that the fibrils were neurotoxic. Increasingly, it has become apparent that these amyloidogenic proteins also self-assemble into a variety of soluble nonfibrillar oligomeric species, and that these oligomeric species may be the most damaging to cells.

Intrinsically disordered proteins such as b-amyloid or a-synuclein must partially fold in order to aggregate. On the other hand, proteins with a stable native fold undergo partial unfolding prior to aggregation. One could argue that amyloidogenesis is attributable to a too-small difference between the stability of the native state (whether intrinsically disordered or stably folded), and the stability of the alternatively folded aggregated state. Although the native proteins are conformationally diverse, aggregates from different proteins are conformationally convergent. These structural features uniquely arise during the course of self-assembly of amyloidogenic proteins and are not present in the native unaggregated state. Given this, we argue that aggregation of amyloid proteins is a structure-based, rather than a sequence-based, homotypic (self) association. Furthermore, since structure rather than sequence is the common feature shared by amyloid aggregates, it seems reasonable to imagine that heterotypic (non-self) as well as homotypic association of amyloidogenic proteins is possible. In this talk I will present our hypothesis that, whereas homotypic association leads to amyloid aggregates, heterotypic association of amyloidogenic proteins may regulate and inhibit amyloid fibril formation. We will present three case studies to illustrate these ideas. These studies include: (1) a comparison of polyasparagine versus polyglutamine aggregation pathways, and a biological motivation for the different pathways, (2) the competing roles of cystatin C as an inhibitor of beta-amyloid aggregation and an inhibitor of the enzyme that degrades beta-amyloid and (3) the design of anti-amyloid peptides that mimic the structure of the amyloidogenic protein transthyretin.