Amyloid Regulatory Networks

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

CBET-1262729 Murphy Diseases such as Alzheimer's, Parkinson's, and diabetes are distinctly different in etiology, symptoms, and progression. Yet they share one common feature: the deposition of proteins on affected organs. The deposited proteins are unique to each disease, and their normal shape and function are distinctly different. Yet, in each case, the proteins undergo a change in shape and structure, causing them to stick together into clumps of fibrillar aggregates. The process of converting normal soluble proteins to insoluble fibrillar aggregates is called amyloidogenesis. The deposits in each disease are comprised mainly of a single protein, unique to each disorder; in other words, the deposits are formed through 'self' association. This self-association arises as a result of the structural features that the proteins adopt at some point during the amyloidogenesis process. These structural features arise in all proteins on the amyloid pathway, at an intermediate point along the pathway, no matter what the disease. The similarity of structural features could lead to 'non-self' association: association between two different proteins that are both at a similar intermediate point. Data with one pair of such proteins, transthyretin (involved in senile systemic amyloidosis) and beta-amyloid (Alzheimer's disease), demonstrate clearly that such non-self association does exist. Furthermore, the binding of transthyretin to beta-amyloid halts beta-amyloid aggregation and, more importantly, prevents beta-amyloid from killing neuron cells. In this project, the examination of non-self association between amyloidogenic proteins will be expanded beyond transthyretin and beta-amyloid. About 100 different pairs of proteins will be probed to determine if the proteins interact. If the answer is yes, experiments will be conducted to define the specific parts of the proteins that are involved in the interaction, and to measure the effect of the interaction on progress along the amyloidogenesis pathway. The hypothesis underlying this project is that a regulatory network exists, that this network contains many amyloidogenic proteins, and that 'non-self' interactions are important in intervening in 'self' interactions. As with transthyretin and beta-amyloid, such 'non-self' interactions may prevent the toxicity that arises due to 'self' interaction. If successful, no longer will scientists think about protein aggregation as an isolated event involving a single protein, but rather, as a network of interacting proteins that co-regulate each other's self-association. Results from this project could contribute innovative new strategies for combating these protein aggregation disorders.