The intrinsically disordered N-terminal domain of the mammalian prion protein as an integrator of neuroprotective and neurotoxic signaling
Cell Biology
Final Report Abstract
The interaction of the cellular prion protein (PrPC) with pathogenic protein conformers, such as PrPSc, Aβ and a-synuclein can activate neurotoxic pathways in the absence of infectious prion propagation. This activity is interconnected with a physiological function of PrPC as an activator of neuroprotective signaling pathways since both neuroprotective and neurotoxic signaling are linked to the unstructured N-terminal domain of PrPC (N-PrP). To provide new insights into underlying mechanisms the research proposal will identify novel ligands of N- PrP and how pathogenic interactors misuse PrPC for toxic signaling. In addition, we will analyze the role of proteolytic processing of PrPC as a switch in regulation and expanding PrP activity and study the PrP interactome under physiological and pathophysiological conditions in vivo. Finally, we will investigate the coevolution of the N-terminal domain of PrPC in tetrapods and its activity to support neurotoxic and neuroprotective signaling pathways. The experimental approaches include in vitro assays, mammalian cell culture models, including primary neurons, and mouse models of neurodegenerative diseases to address the following specific aims.
Publications
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Biological Functions of the Intrinsically Disordered N-Terminal Domain of the Prion Protein: A Possible Role of Liquid–Liquid Phase Separation. Biomolecules, 11(8), 1201.
Polido, Stella A.; Kamps, Janine & Tatzelt, Jörg
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Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies. Science Advances, 7(48).
Linsenmeier, Luise; Mohammadi, Behnam; Shafiq, Mohsin; Frontzek, Karl; Bär, Julia; Shrivastava, Amulya N.; Damme, Markus; Song, Feizhi; Schwarz, Alexander; Da Vela, Stefano; Massignan, Tania; Jung, Sebastian; Correia, Angela; Schmitz, Matthias; Puig, Berta; Hornemann, Simone; Zerr, Inga; Tatzelt, Jörg; Biasini, Emiliano ... & Glatzel, Markus
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Remodeling of the Fibrillation Pathway of α‐Synuclein by Interaction with Antimicrobial Peptide LL‐III. Chemistry – A European Journal, 27(46), 11845-11851.
Oliva, Rosario; Mukherjee, Sanjib K.; Ostermeier, Lena; Pazurek, Lilli A.; Kriegler, Simon; Bader, Verian; Prumbaum, Daniel; Raunser, Stefan; Winklhofer, Konstanze F.; Tatzelt, Jörg & Winter, Roland
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The N-terminal domain of the prion protein is required and sufficient for liquid–liquid phase separation: A crucial role of the Aβ-binding domain. Journal of Biological Chemistry, 297(1), 100860.
Kamps, Janine; Lin, Yu-Hsuan; Oliva, Rosario; Bader, Verian; Winter, Roland; Winklhofer, Konstanze F. & Tatzelt, Jörg
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Hydration makes a difference! How to tune protein complexes between liquid–liquid and liquid–solid phase separation. Physical Chemistry Chemical Physics, 25(41), 28063-28069.
Ramos, Sashary; Kamps, Janine; Pezzotti, Simone; Winklhofer, Konstanze F.; Tatzelt, Jörg & Havenith, Martina
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Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases. Acta Neuropathologica, 148(1).
Song, Feizhi; Kovac, Valerija; Mohammadi, Behnam; Littau, Jessica L.; Scharfenberg, Franka; Matamoros, Angles Andreu; Vanni, Ilaria; Shafiq, Mohsin; Orge, Leonor; Galliciotti, Giovanna; Djakkani, Salma; Linsenmeier, Luise; Černilec, Maja; Hartman, Katrina; Jung, Sebastian; Tatzelt, Jörg; Neumann, Julia E.; Damme, Markus; Tschirner, Sarah K. ... & Altmeppen, Hermann C.
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Liquid–liquid phase separation of the prion protein is regulated by the octarepeat domain independently of histidines and copper. Journal of Biological Chemistry, 300(6), 107310.
Kamps, Janine; Bader, Verian; Winklhofer, Konstanze F. & Tatzelt, Jörg
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Regulated Proteolysis Induces Aberrant Phase Transition of Biomolecular Condensates into Aggregates: A Protective Role for the Chaperone Clusterin. Journal of Molecular Biology, 436(23), 168839.
Kamps, Janine; Yuste-Checa, Patricia; Mamashli, Fatemeh; Schmitz, Matthias; Herrera, Maria Georgina; da Silva, Correia Susana Margarida; Gogte, Kalpshree; Bader, Verian; Zerr, Inga; Hartl, F. Ulrich; Bracher, Andreas; Winklhofer, Konstanze F. & Tatzelt, Jörg
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Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases. Proceedings of the National Academy of Sciences, 122(1).
Gogte, Kalpshree; Mamashli, Fatemeh; Herrera, Maria Georgina; Kriegler, Simon; Bader, Verian; Kamps, Janine; Grover, Prerna; Winter, Roland; Winklhofer, Konstanze F. & Tatzelt, Jörg
