Using C. elegans to Monitor Proteostasis Imbalances

TOPICAL COLLECTIONS

Using C. elegans to Monitor Proteostasis Imbalances

Guest Editors

Carmen Nussbaum-Krammer

Heidelberg University

Dr. Carmen Nussbaum-Krammer is a project group leader at the Center for Molecular Biology of Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), where her group is associated with the laboratory of Prof. Bernd Bukau. She performed her thesis work on prions in the laboratories of Prof. Ina Vorberg and Prof. Hermann Schätzl at the Technical University of Munich. She found that the yeast prion domain Sup35NM could propagate as a prion in neuroblastoma cells, despite the lack of the chaperone Hsp104, which is essential for prion propagation in yeast. This work provided proof of principle that mammalian cells can support cytosolic prion propagation. After obtaining her PhD, she joined the laboratory of Prof. Richard Morimoto at Northwestern University, Evanston (USA), to establish a genetic prion model using Caenorhabditis elegans. She could show that the Sup35NM prion domain exhibits prion-like properties when expressed in the multicellular organism C. elegans and adapts to different requirements for propagation that involve the autophagy-lysosome pathway to transmit cytosolic aggregation-prone proteins between tissues. Dr. Nussbaum-Krammer’s main research interest is to understand the mechanisms underlying the propagation and toxicity of misfolded proteins associated with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.

Cindy Voisine

Northeastern Illinois University

Dr. Cindy Voisine is an Associate Professor of Biology at Northeastern Illinois University. She obtained her PhD in Biomolecular Chemistry from the University of Wisconsin at Madison with Dr. Elizabeth Craig where she studied the role of molecular chaperones in mitochondrial protein import. Dr. Voisine found that the motor function of the mitochondrial Hsp70 cannot be explained by passive trapping alone but includes an essential ATP-dependent interaction with the mitochondrial peripheral protein Tim44 to generate a pulling force and unfold preproteins. Dr. Voisine applied the fundamental principles of protein folding to neurodegenerative disease research during her postdoctoral training in the laboratories of Dr. Anne Hart and Dr. Richard Morimoto. During this time, she identified a subnetwork of chaperones that safeguards proteostasis in aging and neurodegenerative disease. Currently, she investigates the molecular mechanisms of protein misfolding diseases such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease using C. elegans as a model system.

Collection Overview

Protein homeostasis, or ‘proteostasis’, is fundamental to cellular and organismal health. Conserved cellular processes cooperate to maintain a properly folded proteome by influencing protein synthesis, folding and clearance. Cells respond to proteostasis imbalances by activating the Heat shock response, the unfolded protein response (UPR) and the oxidative stress response (OxR) to readjust the cellular proteome. Alterations in proteostasis have been linked to age-related neurodegenerative diseases and cancers. Based on the high level of conservation, model systems such as C. elegans have been instrumental in understanding the role of proteostais in human health and disease. C. elegans possess many characteristics that make it an ideal experimental model including its short lifecycle, transparent cuticle and ease of chemical and genetic manipulations.

This collection will provide methodological strategies to monitor proteostasis at the cellular and organismal level in C. elegans. Stressors, such as misfolded disease proteins, can be experimentally introduced into specific tissues types while cellular and organismal response to proteotoxicity are monitored over time. Proteotoxicity leads to cellular dysfunction that can be quantitatively measured by phenotypic changes. Furthermore, activation of protective pathways in response to proteotoxic stress can be observed using fluorescent reporters. Genetic modifications and chemical treatments can then be employed to determine their effectiveness in readjusting proteostasis. The outcome of this series will provide a toolkit for probing and monitoring proteostasis, evaluating quality control systems that maintain a folded proteome, and investigating the dysregulation of these systems that lead to disease.