Natalia Kononenko

FM | Center for Physiology & Pathophysiology (UoC)

Prof. Dr. Natalia Kononenko CECAD Cologne
Prof. Dr. Natalia Kononenko

Principal Investigator
Professor for cellular and molecular Physiology

Research Areas

2
3

Cellular and Molecular Mechanisms of Neurodegeneration

Our lab integrates molecular, genetic and cell biology approaches with live cell imaging and in vivo neuroanatomy techniques to understand the role of membrane trafficking and autophagy in the pathogenesis of age-dependent neurodegenerative diseases.

Research Focus

The dysfunction of autophagy in the brain is accompanied by the accumulation of insoluble protein inclusions, but the prevention of inclusion formation does not suppress neurodegeneration in autophagy-deficient mice. This challenges the doctrine of protein aggregate removal as a sole function of neuronal autophagy and raises the question: “What is the precise physiological role of autophagy in the brain”? Our lab is uniquely positioned to explore this question by integrating state-of-the-art genetic and cell biology approaches with live-cell imaging and neuroanatomy. Using this multidisciplinary approach, we discovered that autophagy functions in the brain to regulate axonal microtubule dynamics independently of its role in protein degradation. We found that autophagy proteins, which are crucial for autophagosome expansion, also mediate the intracellular cargo transport in neurons and are important regulators of neuronal-activity dependent gene expression. How autophagy proteins switch from their canonical function in protein degradation to cargo transport regulation is currently unknown. We believe that our studies could revolutionize our understanding of molecular mechanisms of neurodegeneration.

Our Goals

Increased induction of autophagy is relatively frequent in neurodegenerative diseases. While increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival, growing evidence indicate that too much autophagic activity can be detrimental and lead to neuronal death. The long-term goal of Dr. Kononenko’s lab is to understand the role of autophagy in the pathology of neurodegenerative diseases. To reveal the role of autophagy in the brain areas selectively vulnerable to neurodegeneration, the group of Dr. Natalia Kononenko aims to develop mouse models for monitoring autophagic turnover rates in the brain in vivo. Given the therapeutic potential of autophagy modulation in neurodegenerative disease, the research performed by Dr. Kononenko’s group may provide new therapeutic targets for treatment of age-associated neurodegenerative disorders.

“The reward of the scientist is the emotional thrill of being the first person in the history of the world to see something or to understand something. Nothing can compare with that experience” – Cecilia Payne-Gaposchkin

Dr. Natalia Kononenko and her co-workers have contributed to the understanding of the molecular and cell biological regulation of autophagosomal trafficking in neurons. The group has identified the endocytic adaptor protein complex-2 (AP-2) as a novel adaptor for autophagosomal trafficking in neurons (Bera et al., 2020) and discovered the role in regulation of microtubule dynamics (Negrete-Hurtado et al., 2020) and synaptic PKA signaling (Overhoff et al., 2022).

Key research questions:

  • Do autophagy and endocytosis regulate neuronal survival independently of their known functions in protein (and organelle) homeostasis?
  • Neuronal cell type-specific functions of autophagy and their role in animal physiology across the life span.

Major research projects:

  • Metabolic rewiring at autophagy-deficient synapses.
  • Role of nutrition in synaptic signaling.
  • Role of the autophagy-endolysosomal system in selective brain vulnerability and their relevance for AD and PD.

Key Publications


  1. Overhoff, M., F. Tellkamp, S. Hess, J. Tutas, M. Tolve, M. Faerfers, L. Ickert, M. Mohammadi, E. De Bruyckere, E. Kallergi, A. Dell Vedove, V. Nikoletopoulou, B. Wirth, J. Isensee, T. Hucho, D. Puchkov, D. Isbrandt, M. Krüger, P. Kloppenburg,Kononenko NL (2022). Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse. EMBO Journal 41:  e110963. DOI:10.15252/embj.2022110963. Corresponding author.
     
  2. Negrete A, Overhoff M, Bera S, De Bruyckere E, Schätzmüller K, Kye MJ, Qin C., Lammers M, Kondylis V, Neundorf I, Kononenko NL (2020). Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons. Nature communications11: 1535. DOI:10.1038/s41467-020-15287-9. Corresponding author.
     
  3. Bera S, Santiago Camblor-Perujo, Calleja-Barca E, Negrete-Hurtado A, Racho J, De Bruyckere E, Wittich C, Ellrich N, Martins S, Adjaye J, Kononenko NL. (2020). AP‐2 reduces amyloidogenesis by promoting BACE 1 trafficking and degradation in neurons. EMBO Reports21(6):e47954. DOI: 10.15252/embr.201947954. Corresponding author.
     
  4. Kononenko NL#, Claßen GA, Kuijpers M, Puchkov D, Maritzen T, Tempes A, Malik AR, Skalecka A, Jaworski J, Haucke V# (2017). Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration. Nature communications, 8:1-16. DOI:10.1038/ncomms14819. Corresponding author.
     
  5. Kononenko NL, Puchkov D, Classen GA, Walter AM, Pechstein A, Sawade L, Kaempf N, Trimbuch T, Lorenz D, Rosenmund C, Maritzen T, Haucke V. (2014). Clathrin/AP-2 Mediate Synaptic Vesicle Reformation from Endosome-like Vacuoles but Are Not Essential for Membrane Retrieval at Central Synapses. Neuron82: 981-988. DOI:10.1016/j.neuron.2014.05.007. First author.
Prof. Dr. Natalia Kononenko CECAD Cologne
Prof. Dr. Natalia Kononenko

Principal Investigator
Professor for cellular and molecular Physiology

Research Areas

2
3