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Faculty of Biology, Chemistry & Earth Sciences

Cell Biology & Electron Microscopy – Prof. Dr. Benedikt Westermann / Prof. Dr. Stefan Geimer / Dr. Till Klecker

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Research Braun Group​: Modeling neurodegeneration in yeast

Neurodegeneration is characterized by the disease-specific loss of neuronal activity, which may culminate in the irreversible destruction of neurons. Imbalances in cellular homeostasis, e.g., homeostasis of organelles and proteins, lead to neuronal dysfunction and neuronal cell death. Neuronal cell death can proceed via distinct subroutines such as apoptosis and necrosis. However, the molecular mechanisms which lead to cell death and how cell death is eventually executed remain poorly understood. Saccharomyces cerevisiae is an established model for evolutionary conserved mechanisms of cellular homeostasis and programmed cell death. We are using yeast models for several neurodegenerative disorders, including Alzheimer’s disease, frontotemporal dementia and motor neuron disease. Heterologous expression of human proteins implicated in these disorders triggers growth deficits, loss of clonogenic survival, induction of oxidative stress, apoptosis and necrosis in yeast. We aim at the mechanistic dissection of the cellular and molecular pathways culminating in yeast cell death. We focus on the role of mitochondria, which are highly dynamic organelles involved in many important cellular pathways, such as respiration, metabolism and programmed cell death. In addition, we are interested in proteolytic pathways, including the ubiquitin-proteasome system, the endolysosomal (or endosomal-vacuolar) pathway and autophagy. These pathways are required for general protein homoestasis but are potentially also involved in the turnover of the human neurotoxic proteins of interest. We trust that the mechanisms described in yeast will enable the targeted validation in higher model organisms, and will therefore contribute to a better understanding of human neurodegenerative disorders.​


Linking mitochondrial dynamics and neurotoxicity in yeast cell death models (DFG BR 3706/3-1, 07/2012-06/2016)

Mitochondria are key organelles in programmed cell death. They constantly fuse and divide, and are subject to degradation and biogenesis. These processes influence neuronal dysfunction and cell death in neurodegenerative disorders. This project aims at a better understanding of the poorly investigated causal links between these processes. For this purpose, an easy-to-handle and genetically tractable yeast cell system will be used, in which molecular mechanisms of programmed cell death, as well as of mitochondrial dynamics and turnover can be precisely analyzed (Figure 1). Our previous work revealed that expression of neurotoxic proteins in yeast result in programmed cell death with critical mitochondrial contribution. In this project, we will express different neurotoxic proteins associated with various neurodegenerative disorders:​

  • We will describe mitochondrial damage and the induction of mitochondrion-dependent cell death pathways.
  • We will define the consequences on mitochondrial morphology and dynamics, and their role in executing cell death.
  • We will investigate pathways of mitochondrial turnover, and dissect their role in providing cytotoxicity.

We trust to elucidate novel cellular mechanisms of neurotoxic cell death in yeast, enabling the targeted validation of these concepts in other model systems for cell death in the human disorders.


Figure 1: Mitochondrial dynamics, turnover, and mitochondrion-dependent cell death. Mitochondria are part of a network promoted by fusion or are fragmented into individual organelles by fission. They are transported along the cytoskeleton. Damaged mitochondria produce reactive oxygen species (ROS) or release proteins into the cytosol, including cytochrome c, yeast endonuclease G (Nuc1) and apoptosis-inducing factor 1 (Aif1), triggering apoptosis and necrosis. Mitophagy and proteasome-dependent pathways, involving cell division cycle protein 48 (Cdc48) and Vms1 [VCP (valosin-containing protein) (p97)/Cdc48-associated mitochondrial-stress-responsive 1], remove damaged mitochondria. Neurotoxic proteins trigger mitochondrial damage and cell death by poorly understood mechanisms: they could interfere with mitochondrial fusion, fission, and motility, or could interrupt with mitochondrion turnover, or could directly affect mitochondrial function.

Linking proteolytic pathways and neurotoxicity in yeast cell death models (e.g., DGM Br2/1, since 10/2016)

Protein homeostasis is very important for cellular fitness and survival. Impaired protein homeostasis has been proposed to be a major driver of neurodegenerative disorders. Several evolutionary conserved proteolytic pathways exist for the removal of damaged, aggregated, mislocalized or surplus proteins. These include the ubiquitin-proteasome system, the endolysosomal (or endosome-vacuolar) pathway and autophagy. Our previous work revealed that the human motor neuron disease-associated protein TDP-43 is degraded via the endosomal-vacuolar pathway and autophagy (Leibiger C. et al., Hum Mol Genet 2018). Notably, TDP-43 impairs the endosomal-vacuolar pathway, thereby interfering with its own degradation and with vacuolar proteolytic activity, which requires endosomal-vacuolar pathway activity. Although autophagy contributes to TDP-43 clearance, its induction surprisingly increases TDP-43 lethality. Thus, the endosomal-vacuolar pathway activity is pivotal for alleviating TDP-43-triggered cytotoxicity. Currently, we are interested in answering the following questions:

  • What is the molecular machinery that determines whether TDP‑43 is degraded via the endosomal-vacuolar pathway or via autophagy (or via the ubiquitin-proteasome system)?
  • What is the molecular machinery that recruits TDP‑43 into late endosomes for degradation via the endosomal-vacuolar pathway?
  • Does the observed inhibitory effect of TDP‑43 on endosomal-vacuolar pathway activity and vacuolar proteolytic activity convert autophagy from cytoprotective to cytotoxic?

We trust being able to contribute to a better understanding how disease-causing TDP-43 species can be efficiently eliminated in cells with possible implications for neuronal survival in human disease.


  • Prof. Dr. Sabrina Büttner, Department of Molecular Biosciences, University of Stockholm, Stockholm, Sweden
  • Dr. Verónica I. Dumit, Head of Core Facility Proteomics, University of Freiburg, Freiburg, Germany
  • Prof. Dr. Denis Gris, Department of Immunology, University of Sherbrooke, Sherbrooke, Québec, Canada
  • Dr. Fred W. van Leeuwen, Department of Cellular Neuroscience, University of Maastricht, Maastricht, The Netherlands
  • Prof. Dr. Frank Madeo, Institute of Molecular Biosciences, University of Graz, Graz, Austria

Selected References

Leibiger C. et al., Hum Mol Genet 2018; in press.

Braun R.J. et al., Cell Rep 2015; 10(9): 1557-1571.

Braun R.J., Front Mol Neurosci 2015; 8:8.

Braun R.J., Front Oncol 2012; 2:182.

Braun R.J. et al., J Biol Chem 2011; 286(22): 19958-19972.

Braun R.J. et al., Trends Biochem Sci 2010; 35(3): 135-144.

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