Many neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and Prion disease, are associated with protein misfolding. In each of these diseases, an endogenous protein misfolds and further converts the normal protein to the misfolded form. How the cellular milieu contributes to the misfolding of these proteins remains unclear. Our interests lie in understanding the cellular mechanisms that contribute to the development of these diseases. We will use Yeast prions as an experimental system to understand the different stages of prion formation. Our previous work was the first to show that two classes of genes affect prion formation at different steps. One class of genes is involved in the initial misfolding phases that lead to aggregation of the protein, whereas the other class is important in later steps of prion formation, which includes the transmission of newly misfolded aggregates to daughter cells. These genes encode proteins that are involved in actin polymerization and appear to be required to maintain normal vacuolar morphology. The focus of this project will specifically address how actin polymerization and the vacuole impact the multistep process of prion formation.
In specific aim 1, we will focus on one of our genes, BEM1, which encodes for a scaffold protein involved in actin polymerization at the bud site and the vacuole. We will test our hypothesis that Bem1p mediated actin networks aid in the transmission of prion particles to the daughter cell.
Aim 2 will investigate how perturbations in vacuole morphology associated with our deletions impacts the integrity of the insoluble protein deposit, a site associated with newly formed prion particles. In our last aim, we will investigate how one of our deletions, vps5, affects the formation of the newly misfolded prion protein. Together, the specific aims will dissect the role that actin networks and the vacuole play in prion formation.

Public Health Relevance

Prion diseases, which include Creutzfeldt-Jakob disease and Mad Cow disease in cattle, are debilitating neurodegenerative disorders caused by infectious misfolded proteins. Our proposed project will focus on how cellular factors, such as the actin cytoskeleton and the vacuole, contribute to the formation of prions. Understanding how prions appear and what cellular factors are involved will provide insight into the etiology of the disease and provide targets for the development of therapies that prevent the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM109336-01
Application #
8626550
Study Section
Intercellular Interactions (ICI)
Program Officer
Wehrle, Janna P
Project Start
2014-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2016-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$343,140
Indirect Cost
$115,140
Name
Marquette University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
046929621
City
Milwaukee
State
WI
Country
United States
Zip Code
53201