Research Projects

 

Endoplasmic reticulum stress and Huntington's disease

Huntington’s disease (HD) is an incurable neurodegenerative disease affecting one in every 7,000 Canadians. Several studies, including my own, identified defects in protein folding environment of the endoplasmic reticulum (ER) as an important modulator of the toxicity of the mutant huntingtin protein (mHtt) responsible for HD. My work as well as other studies showed that accumulation of misfolded proteins in the ER of neuronal cells is one of the few measurable features present in tissue culture and animal models of HD, as well as in human patients samples. I therefore envision that modulation of coping mechanisms that respond to misfolded protein accumulation can be targeted to improve cell viability in HD. However, mechanistic insights on how misfolded protein stress can impact on mHtt toxicity are needed for the development of new therapeutic strategies. Proper folding and quality control of secretory proteins are crucial to cell viability. Cells activate the unfolded protein response (UPR) to cope with aberrant misfolded protein accumulation in the ER (ER stress), but excessive UPR can trigger apoptosis and causes neuronal cell death in models of HD. The overall goal of the project is to determine the mechanisms regulating a cell’s ability to resolve ER stress by combining yeast genetics and mammalian models of HD.

 

 

Misfolded stress responses during chronological aging in yeast. (In collaboration with the Duennwald lab)

Failure to correctly fold proteins is associated with loss of protein function and cell death. All cellular compartments thus evolved response pathways such as the Heat Shock Response (HSR) in the cytoplasm5 and the Unfolded Protein Response (UPR) the endoplasmic reticulum (ER), to insure proper protein folding. Our previous work showed that misfolded polyQ proteins impair HSR signaling and cause excessive UPR induction. Yet how dysregulation of these stress response pathways affects lifespan, healthy aging, and age-dependent polyQ toxicity remains unclear. We will use a well-characterized, genetically and biochemically tractable HD yeast model for biochemical assays, quantitative live cell imaging, genetic screens and transcriptional profiling to identify age-dependent modifiers of polyQ toxicity and later evaluate the expression of these markers  in post-mortem samples of HD patients.

 

 

Yeast cells expressing a sfGFP-tagged version of the ER chaperone Kar2.

Q25-GFP

Q103-GFP

PC12 cells expressing Q25 or Q103 mHtt exon1-GFP. Polyglutamine expansion results in increased aggregation of the protein in the cytoplasm of neuronal cells. 

Your theory is crazy, but it's not crazy enough to be true.

Niels Bohr

© 2014 by Patrick Lajoie.
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Department of Anatomy and Cell Biology

University of Western Ontario

London, ON N6A 5C1 CANADA

plajoie3@uwo.ca

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