Alternative folding of soluble proteins induced by Aβ42 and Tau in aged cells

ABSTRACT One of the major goals of Alzheimer’s disease (AD) research is to understand how aging and the aggregation of Aβ and/or hyperphosphorylated Tau disrupt the proteostasis and cause progressive neuronal death. The current paradigm of AD research focuses on the amyloid aggregation of Aβ/Tau and the proteins sequestrated by these

aggregates. A key untouched question of proteostasis is whether the folding and conformation of soluble proteins, which represent >99% of the proteome, are also changed during aging and AD. As protein conformation determines the specific cellular function(s) of a given protein, the changes in protein folding and conformation

will disrupt the original protein functions or allow some polypeptides to acquire age-/AD-specific functions. Nascent polypeptides take kinetically and thermodynamically favorable routes during de novo folding. The energy landscape that determines the folding paths and final native conformations of a protein is shaped by the

physiochemical environment surrounding the nascent peptide. Using Saccharomyces cerevisiae (budding yeast) as a model organism and a novel proteomics-structure pipeline, our preliminary studies revealed that changing the cellular folding environment induces the alternative folding of many proteins. As changes in the proteome

composition and metabolic profile, two key components of the cellular folding environment, are conserved hallmarks of aging and AD, the goal of this proposal is to understand how aging and AD affect the folding and conformation of the soluble proteins. We propose to use budding yeast for this pilot project as it is a common

model organism used to study cellular and molecular mechanisms of aging. Yeast shares numerous biological processes with animals and develops age-related cellular dysfunctions similar to human aging. In addition, the yeast model of AD has been developed to reveal conserved mechanisms of amyloid aggregation and the cellular

toxicity of Aβ and Tau. Aging is the major risk factor of AD and other age-related dementias. However, previous studies looked at the young yeast cells expressing human Aβ/Tau proteins. In this proposed project, we want to combine the strength of aging and AD research in yeast to find alternative protein folding induced by Aβ42/Tau

in aged cells. We intend to accomplish our goal by 1) determining the prevalence of protein alternative folding induced by aging, and 2) dissecting the effect of Aβ42/Tau on protein folding in aged cells. The hits from our project will be a resource for researchers in the field to determine the gain or loss of protein functions associated

with these alternative folding of proteins. This work is expected to reveal the first 3D view of the proteome affected by aging and Aβ42/Tau.