Protein aggregation is a major pathological hallmark of neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD);and the role of some form of misfolded protein (oligomer or inclusion of ?-amyloid peptide or tau) in inducing a cascade of events that produces symptoms is largely undisputed. Although originally a 'one protein aggregate, one cause, one disease'hypothesis was the dominant ideology, over the last decade it has become clear that these disorders are more heterogeneous with multiple protein aggregates present in any one specific disease. In most cases, the mixed pathology involves proteins that have been identified as intrinsically vulnerable to self-seeded misfolding and aggregation (TDP-43 is an example). The mechanisms that underlie the appearance of these mixed pathologies is poorly understood with a leading hypothesis being that the accumulation of one misfolded and aggregating protein negatively impacts the function of the network of activities that mediate protein folding and degradation (the proteostasis network). Loss of proteostasis function is proposed to lead to secondary misfolding of vulnerable proteins. We propose to test the hypothesis that the accumulation of Alzheimer-type amyloid and FTLD-type neurofibrillary tangles can induce the aggregation of a secondary "reporter" protein that is inherently vulnerable to misfolding and aggregation in transgenic mouse models. Mice that express the reporter, which consists of a variant of superoxide dismutase 1 fused to yellow fluorescent protein (SODG85R:YFP), at levels just below the threshold to initiate self-seeded aggregation, will be crossed with both mice that develop Alzheimer-like amyloidosis and mice that develop tauopathy. Outcomes in these mice will be compared to that of crosses of mice that express SODWT:YFP, which is much less prone to aggregation, with the same amyloid and tauopathy models. For reasons explained within the proposal, we contend that the SOD1-based vectors are well suited for the questions posed by this application. Our goal in these experiments is to establish whether the accumulation of one type of misfolded protein in the mammalian CNS diminishes proteostasis function to such a level that the system fails to prevent the secondary misfolding of other proteins that are intrinsically vulnerable to self-seeded aggregation.
A myriad of activities work in concert as a network to produce, fold, and degrade the proteins that constitute the essential effectors of cellular function. In human neurodegenerative disease, the accumulation of misfolded proteins may disrupt the protein maintenance network and thereby lead to secondary protein folding problems that contribute to disease by further poisoning the system or robbing the cell of vital function. The proposed studies seek to explore the basic tenants of this concept by testing whether the accumulation of protein aggregates that define Alzheimer's disease and tauopathies disrupts the function of this protein maintenance network.