Welcome to the Kikis Lab!
We are located in Spencer Hall at The University of the South in Sewanee, Tennessee. There we study the proteins that underlie various neurodegenerative diseases and use the genetic model system C. elegans to explore the connection between proteostasis decline and disease. Our current project aims to determine whether particulate air pollution acts as a risk factor for Alzheimer’s Disease by triggering proteostasis collapse.
A healthy proteome is one in which the amount of misfolded proteins is minimized. Thus, maintaining the health of the proteome requires tightly balancing protein synthesis, folding, trafficking and clearance. This balance is termed proteostasis and is maintained by a network of proteins referred to as the “proteostasis network” or the “proteostasis machinery”. The process of maintaining proteostasis must be highly dynamic and sensitive to cellular and environmental cues due to a constant flux of destabilized proteins caused by errors in protein synthesis and exposure to acute proteotoxic conditions.
Despite the ability of the proteostasis machinery to readjust its stoichiometry in an attempt to maintain homeostasis, the capacity of cells to buffer against misfolding is strikingly limited. Therefore, the subtle changes in the folding environment that occur during aging can significantly impact the health of the proteome and can trigger neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, or Huntington’s Disease.
Recent findings suggest that particulate air pollution may be a risk factor for Alzheimer’s disease (AD). We hypothesize that small particulate matter produced by the combustion of fossil fuels may be an important source of proteotoxic stress that contributes to the overall misfolded protein load. The resultant imbalance in proteostasis may thus be the direct cause of the observed increased risk for disease. Our thinking on this matter is grounded in the vast body of evidence indicating that AD is a protein folding disorder with Aβ peptide misfolding at its core. Nonetheless, actual samples of particulate air pollution have never been tested for their propensity to trigger protein misfolding.
What is C. elegans?
C. elegans is a non-parastic hermaphroditic nematode about 1mm in length. Adults have less than 1,000 cells, but they nonetheless have a complex body plan including a digestive tract, a reproductive system, neurons, muscle cells, etc. The entire genome is sequenced and gene expression can be knocked down by feeding RNAi-expressing bacteria.
C. elegans has been used in several Nobel Prize winning studies!