The goal of this administrative supplement request is to acquire a new spinning disc confocal microscope to investigate protein aggregation and liquid-liquid phase separation for R35GM119544. The requested instrument will be equally shared between myself, Dr. Amy Hudson (R01GM120735) who studies lysosomal trafficking, and Dr. Blake Hill (R01GM067180) who studies mitochondrial fusion. Proteopathies are a class of at least 71 diseases characterized by the accumulation of protein aggregates. Protein aggregates are caused by an imbalance in protein homeostasis resulting in the accumulation of misfolded proteins. One major question in biomedical research is: How do cells recognize and deal with misfolded proteins? Serendipitously, we found that the model organism Dictyostelium discoideum normally expresses proteins with long polyglutamine tracts that cause one class of proteopathy. We have recently shown that Dictyostelium have an extraordinary ability to resist aggregation of a polyglutamine expanded protein know to aggregate in other model organisms. Here we propose to investigate mechanisms utilized by Dictyostelium to resist polyglutamine aggregation and explore novel aspects of the Dictyostelium protein quality control network.

Public Health Relevance

Numerous diseases are caused by protein aggregation. Currently, no cures for these diseases exist and available treatments mostly focus on treating symptoms, and not the core cause of disease. The studies proposed here may lead to the identification of novel properties of Dictyostelium discoideum that prevent protein aggregation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
3R35GM119544-03S1
Application #
9706278
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cubano, Luis Angel
Project Start
2016-07-15
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Biochemistry
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Santarriaga, Stephanie; Haver, Holly N; Kanack, Adam J et al. (2018) SRCP1 Conveys Resistance to Polyglutamine Aggregation. Mol Cell 71:216-228.e7
Kanack, Adam J; Newsom, Oliver J; Scaglione, Kenneth Matthew (2018) Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP. J Biol Chem 293:2735-2743