The protein-only or prion hypothesis posits that changes in cellular physiology arise from the refolding of host- encoded proteins (prions) to alternative conformations that alter their normal functions. A central event in this process is the assembly of these alternative conformers into ordered amyloid aggregates, which associate with, incorporate, and thereby template the refolding other conformers of the same protein. However, the accumulation of amyloid is a poor predictor of changes in cellular phenotype, and our recent studies reveal that prion, and more generally amyloid, biology likely arises from unique homeostatic niches created by an intersection of multiple, previously unanticipated, and currently poorly understood constraints of the system. This current gap in knowledge is a critical barrier to progress in the field because we are unable to explain, predict and therefore exploit the link between prion misfolding and its phenotypic effects in vivo. Our long-term goal is to bridge this gap by developing a system-based understanding of prion biology that integrates protein quality control pathways, prion protein sequence and conformation, and cell biology. Toward this end, we are exploiting enigmatic aspects of prion biology including sequence variants, dominant negative inhibition, cytoskeletal interactions, strain dominance and prion interactions to reveal the contributors and mechanisms that define balance in the system, create distinct homeostatic niches compatible with each conformational state, and induce transitions along these continuums.

Public Health Relevance

The proposed research is relevant to public health because the misfolding of proteins is associated with a wide array of familial, sporadic and transmissible neurodegenerative diseases, type II diabetes, and familial hypertension in man. Our current understanding of how protein misfolding correlates with disease characteristics and how it can be reversed is limited; thus, our proposed studies are relevant to NIH's mission because the knowledge gained here will inform our understanding of disease dynamics and treatment in man.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
7R35GM118042-03
Application #
9527439
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Maas, Stefan
Project Start
2016-06-01
Project End
2021-05-31
Budget Start
2017-08-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Hadley
State
MA
Country
United States
Zip Code
01035
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Pei, Fen; DiSalvo, Susanne; Sindi, Suzanne S et al. (2017) A dominant-negative mutant inhibits multiple prion variants through a common mechanism. PLoS Genet 13:e1007085
Langlois, Christine R; Pei, Fen; Sindi, Suzanne S et al. (2016) Distinct Prion Domain Sequences Ensure Efficient Amyloid Propagation by Promoting Chaperone Binding or Processing In Vivo. PLoS Genet 12:e1006417