Prof. Dr. Philipp Janker Kahle

Cellular Stresses in Neurodegenerative Diseases and the Role of Ubiquitin

Chronic neurodegenerative diseases are characterized by specific protein aggregates. Protein misfolding is a universal cause of cellular stress, particularly in the very long-lived neurons. Cells have developed many defense mechanisms to cope with this condition. Stress-activated protein kinase pathways induce cytoprotective gene batteries and chaperone defense mechanisms. Sequestration of translationally stalled polysomes into stress granules shall suppress the biosynthesis of misfolded proteins. The ubiquitin-proteasome system and autophagy are catabolic pathways to remove misfolded proteins and aggregates. These mechansisms will be exemplified with regard to frontotemporal dementia and amyotrophic lateral sclerosis, which are characterized by neuropathological aggregates of the protein TDP-43. Another major contributor to age-dependent neurodegeneration is oxidative stress emanating from dysfunctional mitochondria. This is particularly and directly relevant to Parkinson’s disease. The two most common recessive Parkinson’s disease gene products PINK1 and parkin are important for the autophagic removal of damaged mitochondria. The cellular mechanisms regulating mitochondrial quality control will be presented.

Curriculum vitae

Date of Birth: 11.05.1966

University Education

1989                   Dipl. Biochem. ETH Zurich (promoter interaction of T7 RNApol)

1994                   PhD Neurobiol. Univ. Basel (structure / function of nerve growth factor)

2004                   Habilitation LMU Munich (molecular biology and animal models based on the Parkinson’s disease genes encoding α-synuclein

                           and DJ-1)

 

Employment and Positions

1990-1994         graduate student, Natural Sciences at the University of Basel, Switzerland

1994-1998         postdoctoral fellow in the Department of Neurobiology, Stanford University School of Medicine, Stanford (CA), U. S. A.

1998-1999         postdoctoral fellow at the Central Institute for Mental Health, University of Heidelberg, Mannheim, Germany

1999-2006         Senior Scientist, Laboratory of Alzheimer's and Parkinson's Disease Research, Department of Metabolic Biochemistry, Ludwig

                          Maximilians University of Munich, Germany

Head, Parkinson’s Disease Research Group

2006-present    Associate Professor with tenure (W3) Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute

                         for Clinical Brain Research and German Center for Neurodegenerative Diseases, Faculty of Medicine, University of Tübingen,

                         Germany

2019-present    co-affiliated Interfaculty Institute of Biochemistry, Faculty of Science, University of Tübingen, Germany

Ten most important publications

  1. Yamamoto, A., Imai, Y., Takahashi, R., Kahle, P. J., and Haass, C. (2005) Parkin phosphorylation and modulation of its E3 ubiquitin ligase activity. J. Biol. Chem. 280, 3390-3399

  2. Hasegawa, T., Treis, A., Patenge, N., Fiesel, F. C., Springer, W., and Kahle, P. J. (2008) Parkin protects against tyrosinase-mediated dopamine neurotoxicity by suppressing stress-activated protein kinase pathways. J. Neurochem. 105, 1700-1715

  3. Kahle, P. J., Waak, J., and Gasser, T. (2009) DJ-1 and prevention of oxidative stress in Parkinson’s disease and other age-related disorders. Free Radic. Biol. Med. 47, 1354-1361

  4. Geisler, S., Holmström, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J., and Springer, W. (2010) PINK1/parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119-131

  5. Geisler, S., Holmström, K. M., Treis, A., Skujat, D., Weber, S. S., Fiesel, F. C., Kahle, P. J., and Springer, W. (2010) The PINK1/parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6, 871-878

  6. Fiesel, F. C., Weber, S. S., Supper, J., Zell, A., and Kahle, P. J. (2012) TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR. Nucleic Acids Res. 40, 2668-2682 

  7. Hans, F., Fiesel, F. C., Strong, J. C., Jäckel, S., Rasse, T. M., Geisler, S., Springer, W., Schulz, J. B., Voigt, A., and Kahle, P. J. (2014) UBE2E ubiquitin-conjugating enzymes and ubiquitin isopeptidase Y regulate TDP-43 protein ubiquitination. J. Biol. Chem. 289, 19164-19179

  8. Geisler, S., Vollmer, S., Golombek, S., and Kahle, P. J. (2014) UBE2N, UBE2L3 and UBE2D2/3 ubiquitin-conjugating enzymes are essential for parkin-dependent mitophagy. J. Cell Sci. 127, 3280-3293

  9. Wettengel, J., Reautschnig, P., Geisler, S., Kahle, P. J., and Stafforst, T. (2017) Harnessing human ADAR2 for RNA repair – Recoding a PINK1 mutation rescues mitophagy. Nucleic Acids Res. 45, 2729-2808

  10. Hans, F., Eckert, M., von Zweydorf, F., Gloeckner, C. J., and Kahle, P. J. (2018) Identification and characterization of ubiquitinylation sites in TAR DNA-binding protein of 43kDa (TDP-43). J. Biol. Chem. 293, 16083-16099

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