Maintenance of protein homeostasis, or proteostasis, is critical for health. Proteostasis is perturbed in several aging-related diseases including neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's diseases. Caring for patients with these diseases is consuming an increasing fraction of our health care budget. Strikingly, care for Alzheimer's patients alone is responsible for $226 billion in spending per year, and no treatments are available. Thus, new approaches are needed. One such approach involves leveraging the host/pathogen response to infection with intracellular microbes. Our long-term goal is to dissect the mechanisms by which host cells upregulate proteostasis pathways to cope with the increased burden of intracellular infection and replication. Closing this gap in our understanding will provide new insights about proteostasis, and could provide novel treatments for neurodegenerative diseases. Our central hypothesis is that hosts can sense the effects of intracellular infection and increase proteostasis capacity to cope with this increased burden. The objective here is to determine the mechanisms by which the nematode C. elegans upregulates ubiquitin ligase components in response to infection by a natural intracellular microbe that belongs to the microsporidia phylum. Microsporidia commonly infect all animals including humans, and can replicate to very high levels without causing overt effects on the host, likely due to host compensatory mechanisms. Our recent findings indicate that C. elegans upregulates ubiquitin ligase components in response to diverse intracellular infections including microsporidia and virus (Bakowski et al 2014). In unpublished data we have isolated mutants defective in an F-box-related gene (fbxr-1) that constitutively express these ubiquitin ligase components. fbxr-1 mutants have increased pathogen resistance, as well as greatly enhanced thermotolerance and reduced levels of aggregated proteins, indicating improved proteostasis capacity. We hypothesize that C. elegans increases transcription of Skp-Cullin-F-box (SCF) ubiquitin ligase components in order to target misfolded proteins for ubiquitylation and destruction, increasing tolerance of proteotoxic insults.
In Specific Aim 1 we will determine where the Cullin, as well as its upstream negative regulator FBXR-1 act to regulate thermotolerance. We also will perform structure/function analysis on the Cullin to test the hypothesis that it is part of a multi-subunit SCF ubiquitin ligase component.
In Specific Aim 2 we will identify these other SCF ligase components using genetic and biochemical approaches.
In Specific Aim 3 we will determine where FBXR-1 regulates levels of protein aggregates.
In Specific Aim 4 we will perform epistasis and characterize new components of the FBXR-1/Cullin pathway, including a candidate transcription factor. This approach is innovative because it leverages the host response to obligate intracellular infection to understand how proteostasis can be improved. The proposed research is significant because it could lead to new treatments for diseases of compromised proteostasis, such as Alzheimer's disease.
Project Description Neurodegenerative diseases like Alzheimer's disease are responsible for a devastating and increasing burden on our health care system. Defects in proteostasis underlie these aging-related diseases, and new methods are needed to develop treatments. We describe a novel approach whereby the host response to intracellular infection dramatically improves resistance to proteotoxic stressors, which could be leveraged to develop new treatments for aging-related diseases.
| Troemel, Emily (2018) Host-parasite interactions: an interview with Emily Troemel. BMC Biol 16:133 |
| Reddy, Kirthi C; Dror, Tal; Sowa, Jessica N et al. (2017) An Intracellular Pathogen Response Pathway Promotes Proteostasis in C. elegans. Curr Biol 27:3544-3553.e5 |
| Reinke, Aaron W; Mak, Raymond; Troemel, Emily R et al. (2017) In vivo mapping of tissue- and subcellular-specific proteomes in Caenorhabditis elegans. Sci Adv 3:e1602426 |
