Biological Sciences


Camberg, Jodi

Advisor Department

Cell and Molecular Biology




Prion; Chaperone; Protease; Amyloid; Neurodegenerative; ClpXP; Lon; Yeast; Hsp104; Sup35

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Creative Commons License
This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License.


A noted characteristic found in several neurodegenerative disorders, including Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and bovine spongiform encephalopathy, is the accumulation of amyloid plaques in the brain. Amyloid plaques contain deposits of fibrillar aggregates of misfolded proteins that disrupt normal functionality in neurons. Certain variants of these misfolded proteins are self-replicating; these self-replicating amyloids are termed prions (for infectious protein). We are interested in how protein misfolding contributes to amyloid formation and how molecular chaperone proteins can change the formation of amyloid deposits. Chaperone proteins function by catalyzing the proper folding of other proteins, the refolding of misfolded proteins, and the disaggregation of protein aggregates. An example is the ATP-dependent chaperone protein Hsp104 from Saccharomyces cerevisiae (yeast). Overexpression of Hsp104 results in clearance of amyloid deposits of Sup35, a naturally occurring amyloidogenic protein. When expressed at low levels, Hsp104 is also required for propagation of Sup35 prion in daughter cells and prion inheritance.

Due to their amyloid disassembly activity, chaperone proteins may hold significant therapeutic potential for treatment of amyloid-associated neurodegenerative diseases. Therefore, we wanted to engineer a molecular chaperone protein with robust amyloid disassembly activity that can also degrade subunits to prevent them from reentering the pool of amyloidogenic precursors. We focused on ClpXP and Lon proteases from Escherichia coli. ClpX is a chaperone protein related to Hsp104 that is found in bacteria and the mitochondria of eukaryotes, which partners with the protease ClpP. Lon is also a related protease from the AAA+ domain family. We constructed plasmids for expression of ClpXP and Lon in yeast strains containing Sup35. We plan to test if expression of ClpXP or Lon in yeast is associated with clearance of the Sup35 prion phenotype, referred to as [PSI+]. We also plan to perform random mutagenesis of ClpXP and Lon to engineer and select for chaperone-protease complexes that demonstrate enhanced clearance of amyloids in yeast via proteolysis. These studies will help to develop new molecular chaperone based tools that can be used promote in vivo clearance of toxic aggregates and amyloid deposits.